Indole derivative having piperidine ring

ABSTRACT

The present invention relates to a compound represented by the following formula, a pharmacologically acceptable salt thereof, or a use thereof as a pharmaceutical:  
                 
 
wherein R 1  and R 2  are substituents adjacent to each other, and together with two carbon atoms to each of which they attach, form a 5- to 7-membered non-aromatic carbocyclic group or the like, which may be substituted by 1 to 4 substituents selected from (1) an oxo group, (2) a hydroxyl group, and the like; R 3  represents a hydrogen atom or the like; and R 6  represents a hydrogen atom or the like. 
It is an object of the present invention to discover an agent for treating or preventing lower urinary tract symptoms, and particularly symptoms regarding urinary storage, which has a superior strength of binding to a 5-HT1A receptor and an antagonism to the receptor.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority date under the Paris Convention basedon Japanese Patent Applications No. 2004-142437 filed in Japan on May12, 2004, the contents of which are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a compound having ability to bind to aserotonin 1A receptor, and a use thereof as a pharmaceutical. Morespecifically, it relates to an agent for treating or preventing lowerurinary tract symptoms.

2. Description of the Related Art

In the periphery system, serotonin exhibits effects of smooth musclerelaxation, platelet aggregation, and gastrointestinal tract functionregulation. On the other hand, in the central nervous system, serotoninfunctions as a neurotransmitter and is deeply associated with the motorsystem, perceptive system, physiological functions such as bodytemperature regulation, sleep, feeding behavior, vomiting, sexualbehavior, neuroendocrine system, cognition and memory, or biorhythm, andpathologic conditions such as anxiety, aggression, obsession, mooddisorder, hallucination, schizophrenia, autism, or drug dependence(refer to Peroutka S. J., 5-Hydroxytryptamine receptor subtypes, AnnuRev Neurosci. 1988; 11: p.45-60; and H. Matsui, and three others,Neurotransmitter Today, 19(2), 1997, p.131-146, for example).

Serotonin receptor is classified into 7 families ranging from 5-HT1 to5-HT7. 5HT1 is composed of 5 subtypes (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E,and 5-HT1F).

5-HT1A receptor is widely distributed in the central nervous system. Inthe brain, this receptor is distributed at a high density, particularlyin the cerebral limbic system, mainly in the hippocampus, the septum,the amygdaloid complex, and the nuclei raphes. In the spinal cord, it isdistributed at a high density in the posterior horn cortex which primaryafferent fibers project (I and II laminae), the anterior horn innerportion where motoneurons are localized (VIII-IX laminae), and theintermediolateral nucleus where preganglionic sympathetic cells arepresent (VII lamina). In the nerve, a serotonin receptor exists as apresynaptic receptor in the cell bodies of the serotonin nerve (5-HT1Asomatodendritic autoreceptor), and as a postsynaptic receptor, exists onthe nerve in which the serotonin nerve innervates. Such a presynapticreceptor conducts negative feedback regulation to serotonin release.

The action of a 5-HT1A receptor in a living body and diseases in whichthe receptor is involved have been clarified as a result of thediscovery of agonists and antagonists that are selective for the 5-HT1Areceptor.

Depression and anxiety disorder are examples of such diseases. It isconsidered that a presynaptic 5-HT1A receptor is important for treatingdepression. It is considered that a selective serotonin reuptakeinhibitor (SSRI) and a selective serotonin/noradrenalin reuptakeinhibitor (SNRI) that are currently used as therapeutic agents. Theseagents inhibit the uptake of these transmitters in nerve cells, so as toincrease the concentration of the transmitters in a synaptic cleft, andthat as a result, desensitizes a receptor, thereby exhibiting efficacy.Recently, it has been reported that (−) pindolol (which exhibitsaffinity for adrenaline β and 5-HT1A receptor and has an antagonisticeffect against 5-HT1A receptor) promotes the onset of thepharmacological effects of SSRI, thereby increasing the effective ratethereof in patients with depression. This may be because the release ofserotonin at the nerve terminals is increased by the blockage of apresynaptic 5-HT1A receptor, so that the desensitization of the receptoris advanced (refer to Farde L, and four others, PET-Determination ofrobalzotan (NAD-299) induced 5-HT(1A) receptor occupancy in the monkeybrain, Neuropsychopharmacology, 2000 April; 22(4): p. 422-9, forexample).

The study of Barros M. et al. using marmosets is a report suggesting apossibility of the use of a 5-HT1A receptor antagonist for anxietydisorder. Using, as an index, the fear and anxiety behavior of amarmoset provoked by showing the stuffed specimen of a predaceous animalto the marmoset, the effect of a 5-HT1A receptor antagonist on anxietywas studied. As a result, it was shown that this agent has an anxiolyticeffect (refer to Barros M, and seven others, Anxiolytic-like effects ofthe selective 5-HT1A receptor antagonist WAY 100635 in non-humanprimates, Eur J Pharmacol., Dec. 15, 2003; 482(1-3): p. 197-203, forexample). These results suggested a possibility that the 5-HT1A receptorantagonist is useful as an agent for preventing or treating depressionor anxiety disorder.

It has also been strongly suggested that the 5-HT1A receptor isassociated with cognition, memory, and learning. An NMDA-type glutamatereceptor antagonist, or the fornix transection induce cognitivedisorder. Such cognitive disorder was improved by a 5-HT1A receptorantagonist (refer to Harder J A, Ridley RM. The 5-HT1A antagonist, WAY100 635, alleviates cognitive impairments induced by dizocilpine(MK-801) in monkeys.Neuropharmacology. Feb. 14, 2000; 39(4): p. 54⁷-52and Harder J A, and four others, The 5-HT1A antagonist, WAY 100635,ameliorates the cognitive impairment induced by fornix transection inthe marmoset. Psychopharmacology (Berl). 1996 October; 127(3): 245-54,for example). Yasuno F. et al. administered a 5-HT1A receptor antagonistlabeled with ¹¹C ([¹¹C]WAY-100635) to a human. Thereafter, they examinedthe relationship between memory and a portion shared by the 5-HT1Areceptor by positron emission tomography (refer to Yasuno F, and nineothers, Inhibitory effect of hippocampal 5-HT1A receptors on humanexplicit memory, Am J Psychiatry. 2003 February; 160(2): p. 334-40, forexample). As a result, a negative correlation was found between theimprovement of remembrance and the affinity of [¹¹C]WAY-100635 to bindto a hippocampal postsynaptic 5-HT1A receptor. This result suggests thatpostsynaptic 5-HT1A receptors distributed over the hippocampus have anegative effect on the memory. These findings suggest a possibility thata 5-HT1A receptor antagonist is effective for cognitive disorder, ormemory or learning disorder.

Also, in recent years, the association of a 5-HT1A receptor with urinaryreflex has been reported (refer to Lecci A, and three others,Involvement of 5-hydroxytryptamine1A receptors in the modulation ofmicturition reflexes in the anesthetized rat, J Pharmacol Exp Ther.,1992 July; 262(1): p. 181-9, for example).

Various subjective symptoms provoked by urinary dysfunction aregenerically called lower urinary tract symptoms. Such lower urinarytract symptoms are broadly divided into symptoms regarding urinarystorage such as increased urinary frequency, urinary urgency, or urinaryincontinence, and voiding symptoms such as difficulty of urination oranuresis. Urinary incontinence is further classified into stressincontinence, urge incontinence, overflow incontinence, reflex urinaryincontinence, extraurthral incontinence, or the like. Urinaryincontinence having both the symptom of stress incontinence and that ofurge incontinence is called mixed urinary incontinence. In theInternational Continence Society (ICS) that took place in 2001, thefollowing proposal was given: “The overactive bladder is a medicalcondition referring to the symptoms of frequency and urgency, with orwithout urge incontinence, when appearing in the absence of localpathologic or metabolic factors that would account for these symptoms.”Thus, a pathologic condition determined mainly based on subjectivesymptoms was defined as overactive bladder.

Examples of a cause of symptoms regarding urine pooling storage mayinclude neuropathic bladder caused by encephalopathy (includingcerebrovascular disorder, Parkinson's disease, brain tumor, multiplesclerosis, and the like), senile dementia, myelopathy, or spinaldisease, unstable bladder, benign prostatic hyperplasia, prostaticcancer, bladder neurosis, interstitial bladder cystitis, bladderirritation caused by chronic cystitis or chronic prostatitis,cystospasm, enuresis (including nocturnal enuresis), nocturia, andpsychogenic dysuria.

In studies regarding urinary reflex in rats, a 5-HT1A receptor agonistpromotes urinary reflex (refer to Lecci A, and three others, Involvementof 5-hydroxytryptamine1A receptors in the modulation of micturitionreflexes in the anesthetized rat, J Pharmacol Exp Ther., 1992 July;262(1): p. 181-9, for example), whereas a 5-HT1A receptor antagonistsuppresses urinary reflex measured by rhythmical bladder contraction orcystometogram. In addition, in the case of a 5-HT1A receptor partialagonist, the effect to suppress urinary reflex is reduced depending onthe degree of the agonistic action of the agent (refer to Testa R, andnine others, Effect of several 5-hydroxytryptamine(1A) receptor ligandson the micturition reflex in rats: comparison with WAY 100635, JPharmacol Exp Ther., 1999 September; 290(3): p. 1258-69, for example).From these findings, a 5-HT1A receptor antagonist is anticipated as anovel agent for treating symptoms regarding urinary storage based on anovel action mechanism (including increased urinary frequency, urinaryurgency, and urinary incontinence, etc.) (refer to Andersson K E,Pehrson R, CNS involvement in overactive bladder: pathophysiology andopportunities for pharmacological intervention, Drugs, 2003; 63(23): p.2595-611, for example).

Other than the aforementioned diseases, there is a wide range ofdiseases in which a 5-HT1A receptor would be involved. Examples of sucha disease may include neuropsychiatic disorder (e.g.obsessive-compulsive disorder (refer to Bourin M, and another, Thefuture of antidepressants, Biomed Pharmacother., 1996; 50(1): p. 7-12,for example), borderline personality disorder (refer to Hansenne M, andseven others, 5-HT1A dysfunction in borderline personality disorder,Psychol Med. 2002 July; 32(5): p. 935-41, for example), post-traumaticstress disorder (refer to Wilson MS, and another, Effects of fluoxetineon the 5-HT1A receptor and recovery of cognitive function aftertraumatic brain injury in rats, Am J Phys Med Rehabil., 2002 May; 81(5):p. 364-72, for example), panic disorder, schizophrenia (refer toFletcher A, and two others, Silent 5-HT1A receptor antagonists: utilityas research tools and therapeutic agents, Trends Pharmacol Sci., 1993December; 14(12): p. 441-8, for example), genital insufficiency (referto Fletcher A, and two others, Silent 5-HT1A receptor antagonists:utility as research tools and therapeutic agents, Trends Pharmacol Sci.,1993 December; 14(12): p. 441-8, for example), alcohol and/or cocainedependence (refer to Zhou F C, and three others, Additive reduction ofalcohol drinking by 5-HT1A antagonist WAY 100635 and serotonin uptakeblocker fluoxetine in alcohol-preferring P rats, Alcohol Clin Exp Res.,1998 February; 22(1): p. 266-9 and Carey R J, and two others, 5-HT1Aagonist/antagonist modification of cocaine stimulant effects:implications for cocaine mechanisms. Behav Brain Res., Apr. 15, 2002;132(1): p. 37-46, for example), sleep disorder (refer to Fletcher A, andtwo others, Silent 5-HT1A receptor antagonists: utility as researchtools and therapeutic agents, Trends Pharmacol Sci., 1993 December;14(12): p. 441-8, for example), pain (refer to Fletcher A, and twoothers, Silent 5-HT1A receptor antagonists: utility as research toolsand therapeutic agents, Trends Pharmacol Sci., 1993 December; 14(12): p.441-8, for example), migraine (refer to Boers P M, and three others,Naratriptan has a selective inhibitory effect on trigeminovascularneurones at central 5-HT1A and 5-HT(1B/1D) receptors in the cat:implications for migraine therapy, Cephalalgia., 2004 February; 24(2):p. 99-109, for example), visual attention disorder (refer to Balducci C,and four others, Reversal of visual attention dysfunction after AMPAlesions of the nucleus basalis magnocellularis (NBM) by thecholinesterase inhibitor donepezil and by a 5-HT1A receptor antagonistWAY 100635,Psychopharmacology (Berl)., 2003 April; 167(1): p. 28-36, forexample), temperature instability (refer to Fletcher A, and two others,Silent 5-HT1A receptor antagonists: utility as research tools andtherapeutic agents, Trends Pharmacol Sci., 1993 December; 14(12): p.441-8, for example), vomiting (refer to Gupta Y K, and another,Involvement of 5-HT1A and 5-HT2 receptor in cisplatin induced emesis indogs, Indian J Physiol Pharmacol., 2002 October; 46(4): p. 463-7, forexample), gastrointestinal disorder (refer to Fletcher A, and twoothers, Silent-5-HT1A receptor antagonists: utility as research toolsand therapeutic agents, Trends Pharmacol Sci., 1993 December; 14(12): p.441-8, for example), eating disorder (refer to Fletcher A, and twoothers, Silent 5-HT1A receptor antagonists: utility as research toolsand therapeutic agents, Trends Pharmacol Sci., 1993 December; 14(12): p.441-8, for example), hypertension (refer to Dabire H, Central5-hydroxytryptamine (5-HT) receptors in blood pressure regulation,Therapie., 1991 November-December; 46(6): p. 421-9, for example),neuro-degenerative disease (refer to Kruger H, and two others, Effectsof ionotropic glutamate receptor blockade and 5-HT1A receptor activationon spreading depression in rat neocortical slices, Neuroreport., Aug.20, 1999; 10(12): p. 2651-6 and Suchanek B, and two others, The 5-HT1Areceptor agonist BAY x 3702 prevents staurosporine-induced apoptosis,Eur J Pharmacol., Aug. 14, 1998; 355(1): p. 95-101, for example) (e.g.cerebral ischemia, Alzheimer's disease, etc.), dyskinesia caused byParkinson's disease (refer to Bibbiani F, and two others, Serotonin5-HT1A agonist improves motor complications in rodent and primateparkinsonian models, Neurology., Nov. 27, 2001; 57(10): p. 1829-34, forexample), and symptoms associated with withdrawal from nicotineingestion or smoking (refer to Kurt Rasmussen, and sixteen others, TheNovel 5-Hydroxytryptamine1A Antagonist LY426965: Effects on NicotineWithdrawal and Interactions with Fluoxetine, J. of Pharmacol.Experimental Therapeutics., 294: 688-700: (2000), for example).

Accordingly, a 5-HT1A receptor antagonist is expected as an agent forpreventing or treating such a wide range of diseases. Although studiesfor developing such a 5-HT1A receptor antagonist have actively beenconducted, the agent has not yet been on the market. Thus, thedevelopment of a superior 5-HT1A receptor antagonist has been desired.

A large number of reports have previously been made regarding compoundshaving an antagonistic effect against a 5-HT1A receptor. However, forthe use as an agent for treating lower urinary tract symptoms, only afew compounds described in International Publication WO99/06384 andJP-A-2002-114684 have been known.

The compound described in International Publication WO99/06384 is acompound represented by the following formula or a pharmacologicallyacceptable salt thereof:

wherein R represents a hydrogen atom or the like; R¹ represents ahydrogen atom or the like; R² represents a halogen atom or the like; andB represents a monocyclic aryl group or the like. The structuralcharacteristics of this compound are that it has an N-phenylaminoalkylgroup as a piperazine side chain.

Accordingly, in terms of chemical structure, the compound described inInternational Publication WO99/06384 completely differs from thecompound represented by formula (I) of the present inventioncharacterized in that “it has an unsubstituted or monosubstitutedcarbamoyl group at position 6 on an indole skeleton, and has a methoxygroup on an aryl group of an aryl alkyl side chain extended from anitrogen atom on a piperidine ring, at an ortho position to the alkylside chain.”

JP-A-2002-114684 is a prior art that is closest to the presentinvention. This document discloses an agent for treating lower urinarytract symptoms containing a compound represented by the followingformula, a salt thereof, or a hydrate thereof:

wherein the Ar¹ ring represents a benzene ring or the like; D representsa nitrogen atom or the like; R³ and R⁴ identically or differentlyrepresent hydrogen atoms or the like; R⁵ represents a hydrogen atom orthe like; R¹ and R² represent hydrogen atoms or the like, or bind toeach other, so as to form a ring containing X; and m represents 0 or aninteger between 1 and 6.

The compound described in JP-A-2002-114684 is identical to the compoundrepresented by formula (I) described in International PublicationWO98/43956, or the compound described in examples. The structuralcharacteristics of this compound are that “it has an indole or indolineskeleton having a cyclic amine that may be substituted by an arylalkylgroup or the like as a side chain structure.”

Among the compounds disclosed in International Publication WO98/43956,specific examples of compounds that are close to the compoundrepresented by formula (I) of the present invention may include thoserepresented by the following formula:

wherein R¹ and R³ each represent a hydrogen atom; R² represents acarbamoyl group; R⁵ represents an arylalkyl group that may besubstituted; n and m represent 0; p represents 2; T and Z each representa nitrogen atom; and Y represents a methine group. The closest compoundis the compound described in Example 337. However, these disclosedcompounds are limited to compounds, “which have an indole or indolineskeleton having a cyclic amine that may be substituted by an arylalkylgroup or the like as a side chain structure.” There are no descriptionssuggesting the compound represented by formula (I) of the presentinvention, “which has an unsubstituted or monosubstituted carbamoylgroup at position 6 on an indole skeleton, and has a methoxy group on anaryl group of an aryl alkyl side chain extended from a nitrogen atom ona piperidine ring, at an ortho position to the alkyl side chain.”

Accordingly, the compound described in JP-A-2002-114684 differs from thecompound represented by formula (I) of the present invention in terms ofchemical structure, and thus, it does not have a chemical structure thatis specific to the compound of the present invention.

Moreover, JP-A-2002-114684 describes the test methods of a[³H]-8-hydroxy-dipropylaminotetralin binding test (Test example 1), a5-HT1A receptor antagonist test (Test example 2), and a test regardingan antagonistic effect against a 5-HTIA receptor agonist-inducedhypothermia in a rat (Test example 3). However, the document disclosesneither test compounds nor specific test results (pharmacologicaleffects). Thus, it is impossible to grasp the entity of the inventionbased on such descriptions.

Among the compounds described in International Publication WO98/43956and JP-A-2002-114684, the compound that is closest to the compoundrepresented by formula (I) of the present invention is the compounddescribed in Example 337, which is represented by the following formula

As described later in the results of pharmacological studies, thepharmacological effect of this compound is characterized in that it hasaffinity for 5-HT1A but its antagonistic effect against the receptor isweak.

On the other hand, the compound of the present invention represented bythe following formula (I):

is characterized in that it has an unsubstituted or monosubstitutedcarbamoyl group at position 6 on the indole skeleton thereof, and has amethoxy group on an aryl group of an aryl alkyl side chain extended froma nitrogen atom on a piperidine ring, at an ortho position to the alkylside chain, thereby having an increased antagonism to the 5-HT1Areceptor. Therefore, the compound of the present invention has effectsthat are completely different from those of the compounds described inInternational Publication WO98/43956 and JP-A-2002-114684.

It is an object of the present invention to provide a compound havingaffinity for a 5-HT1A receptor and exhibiting an antagonism to thereceptor, which is used for therapeutic purposes.

BRIEF SUMMARY OF THE INVENTION

As stated above, a compound having ability to bind to a 5-HT1A receptorand also having an antagonistic effect against the receptor can beanticipated as an agent for treating lower urinary tract symptoms basedon a novel action mechanism. However, a compound, which has a superiorbinding affinity to a 5-HT1A receptor and an antagonism to the receptor,and which is able to exhibit superior clinical action to treat orprevent lower urinary tract symptoms, and particularly, symptomsregarding urinary storage has not yet been found.

Under such circumstances, the present inventors have conducted intensivestudies. As a result, they have found that a compound described below,which shows binding affinity to a 5-HT1A receptor and has anantagonistic effect against receptor, has excellent inhibitory effect onthe accentuation of urinary reflex caused by superior brain injury andis useful as an agent for treating or preventing lower urinary tractsymptoms, and particularly, increased urinary frequency or urinaryincontinence, thereby completing the present invention.

That is to say, the present invention relates to the followingfeatures 1) to 34):

-   -   1) A compound represented by the following formula (I) or a        pharmacologically acceptable salt thereof:    -   wherein R¹ and R² are substituents adjacent to each other, and        together with two carbon atoms to each of which they attach,        form:    -   (1) a 5- to 7-membered non-aromatic carbocyclic group,    -   (2) a 5- to 7-membered non-aromatic heterocyclyl group,    -   (3) a 6-membered aromatic carbocyclic group, or    -   (4) a 5- or 6-membered aromatic heterocyclyl group, which may be        substituted by 1 to 4 substituents selected from the following        substituent group B1;    -   R³ represents a hydrogen atom or methyl group; and    -   R⁶ represents a substituent selected from the following        substituent group A1,    -   Substituent group A1: (1) a hydrogen atom, (2) a halogen        atom, (3) a cyano group, (4) a hydroxyl group, (5) a nitro        group, (6) a carboxyl group, (7) a C3-C8 cycloalkyl group, (8) a        C2-C6 alkenyl group, (9) a C2-C6 alkynyl group, (10) a C1-C6        alkylthio group, (11) a C1-C6 alkoxycarbonyl group, (12) a C1-C6        alkylsulfonyl group, (13) a C1-C6 alkyl group (wherein the above        described C1-C6 alkyl group may be substituted by 1 to 3        substituents selected from the group consisting of a halogen        atom, a hydroxyl group, and a C1-C6 alkoxy group), (14) a C1-C6        alkoxy group (wherein the above described C1-C6 alkoxy group may        be substituted by 1 to 3 halogen atoms), (15) an amino group        (wherein the above described amino group may be substituted by a        substituent selected from the group consisting of a C1-C6 alkyl        group, a formyl group, a C1-C6 alkanoyl group, and a C1-C6        alkylsulfonyl group), and (16) a carbamoyl group (wherein the        above described carbamoyl group may be substituted by one or two        C1-C6 alkyl groups),    -   Substituent group B1: (1) a hydrogen atom, (2) a halogen        atom, (3) a cyano group, (4) a hydroxyl group, (5) a nitro        group, (6) an oxo group, (7) a carboxyl group, (8) a C3-C8        cycloalkyl group, (9) a C2-C6 alkenyl group, (10) a C2-C6        alkynyl group, (11) a C1-C6 alkylthio group, (12) a C1-C6        alkoxycarbonyl group, (13) a C1-C6 alkylsulfonyl group, (14) a        C1-C6 alkyl group (wherein the above described C1-C6 alkyl group        may be substituted by a halogen atom, a hydroxyl group, and a        C1-C6 alkoxy group), (15) a C1-C6 alkoxy group (wherein the        above described C1-C6 alkoxy group may be substituted by 1 to 3        halogen atoms), (16) an amino group (wherein the above described        amino group may be substituted by a substituent selected from        the group consisting of a C1-C6 alkyl group, a formyl group, a        C1-C6 alkanoyl group, and a C1-C6 alkylsulfonyl group), (17) a        carbamoyl group (wherein the above described carbamoyl group may        be substituted by one or two C1-C6 alkyl groups), (18) a C1-C6        alkoxyimino group, (19) a C5-C6 cycloalkyl group formed by two        C1-C3 alkyl groups attaching to the same carbon atom, and (20) a        tetrahydropyranyl group formed by two C1-C3 alkyl groups        attaching to the same carbon atom, together with an oxygen atom        and the above described carbon atom;    -   2) The compound according to 1) above or a pharmacologically        acceptable salt thereof, wherein R¹ and R² are substituents        adjacent to each other, and together with two carbon atoms to        each of which they attach, form a group represented by the        following formula:    -   wherein a hydrogen atom on each cyclic group may be substituted        by 1 to 4 substituents selected from the following substituent        group B1,    -   Substituent group B1: (1) a hydrogen atom, (2) a halogen        atom, (3) a cyano group, (4) a hydroxyl group, (5) a nitro        group, (6) an oxo group, (7) a carboxyl group, (8) a C3-C8        cycloalkyl group, (9) a C2-C6 alkenyl group, (10) a C2-C6        alkynyl group, (11) a C1-C6 alkylthio group, (12) a C1-C6        alkoxycarbonyl group, (13) a C1-C6 alkylsulfonyl group, (14) a        C1-C6 alkyl group (wherein the above described C1-C6 alkyl group        may be substituted by a halogen atom, a hydroxyl group, and a        C1-C6 alkoxy group), (15) a C1-C6 alkoxy group (wherein the        above described C1-C6 alkoxy group may be substituted by 1 to 3        halogen atoms), (16) an amino group (wherein the above described        amino group may be substituted by a substituent selected from        the group consisting of a C1-C6 alkyl group, a formyl group, a        C1-C6 alkanoyl group, and a C1-C6 alkylsulfonyl group), (17) a        carbamoyl group (wherein the above described carbamoyl group may        be substituted by one or two C1-C6 alkyl groups), (18) a C1-C6        alkoxyimino group, (19) a C5-C6 cycloalkyl group formed by two        C1-C3 alkyl groups attaching to the same carbon atom, and (20) a        tetrahydropyranyl group formed by two C1-C3 alkyl group        attaching to the same carbon atom, together with an oxygen atom        and the above described carbon atom;    -   3) The compound according to 1) above or a pharmacologically        acceptable salt thereof, which is represented by formula        (I-a-1), formula (I-a-2), formula (I-a-3), or formula (I-a-4):    -   wherein R³ represents a hydrogen atom or methyl group;    -   R^(4a) and R^(5a) represent substituents selected from the        following substituent group B1; R⁶ represents a substituent        selected from the following substituent group A1; R^(11a)        represents a hydroxyl group, R^(12a) represents a hydrogen atom        or C1-C6 alkyl group, or R^(11a) and R^(12a) represent a        carbonyl group or the formula C═N-OR^(8c) (wherein R^(8c)        represents a C1-C6 alkyl group), together with carbon atoms to        which R^(11a) and R^(12a) attach;    -   X_(a) represents a methylene group wherein the hydrogen atom of        the above described methylene group may be substituted by a        substituent selected from the following substituent group B1or        oxygen atom; and n_(a) represents an integer between 1 and 3,    -   Substituent group A1: (1) a hydrogen atom, (2) a halogen        atom, (3) a cyano group, (4) a hydroxyl group, (5) a nitro        group, (6) a carboxyl group, (7) a C3-C8 cycloalkyl group, (8) a        C2-C6 alkenyl group, (9) a C2-C6 alkynyl group, (10) a C1-C6        alkylthio group, (11) a C1-C6 alkoxycarbonyl group, (12) a C1-C6        alkylsulfonyl group, (13) a C1-C6 alkyl group (wherein the above        described C1-C6 alkyl group may be substituted by 1 to 3        substituents selected from the group consisting of a halogen        atom, a hydroxyl group, and a C1-C6 alkoxy group), (14) a C1-C6        alkoxy group (wherein the above described C1-C6 alkoxy group may        be substituted by 1 to 3 halogen atoms), (15) an amino group        (wherein the above described amino group may be substituted by a        substituent selected from the group consisting of a C1-C6 alkyl        group, a formyl group, a C1-C6 alkanoyl group, and a C1-C6        alkylsulfonyl group), and (16) a carbamoyl group (wherein the        above described carbamoyl group may be substituted by one or two        C1-C6 alkyl groups), Substituent group B1: (1) a hydrogen        atom, (2) a halogen atom, (3) a cyano group, (4) a hydroxyl        group, (5) a nitro group, (6) an oxo group, (7) a carboxyl        group, (8) a C3-C8 cycloalkyl group, (9) a C2-C6 alkenyl        group, (10) a C2-C6 alkynyl group, (11) a C1-C6 alkylthio        group, (12) a C1-C6 alkoxycarbonyl group, (13) a C1-C6        alkylsulfonyl group, (14) a C1-C6 alkyl group (wherein the above        described C1-C6 alkyl group may be substituted by a halogen        atom, a hydroxyl group, and a C1-C6 alkoxy group), (15) a C1-C6        alkoxy group (wherein the above described C1-C6 alkoxy group may        be substituted by 1 to 3 halogen atoms), (16) an amino group        (wherein the above described amino group may be substituted by a        substituent selected from the group consisting of a C1-C6 alkyl        group, a formyl group, a C1-C6 alkanoyl group, and a C1-C6        alkylsulfonyl group), (17) a carbamoyl group (wherein the above        described carbamoyl group may be substituted by one or two C1-C6        alkyl groups), (18) a C1-C6 alkoxyimino group, (19) a C5-C6        cycloalkyl group formed by two C1-C3 alkyl groups attaching to        the same carbon atom, and (20) a tetrahydropyranyl group formed        by two C1-C3 alkyl group attaching to the same carbon atom,        together with an oxygen atom and the above described carbon        atom;    -   4) The compound according to 3) above or a pharmacologically        acceptable salt thereof, wherein R^(11a) and R^(12a) form a        carbonyl group, together with carbon atoms to which R^(11a) and        R^(12a) attach;    -   5) The compound according to 3) or 4) above or a        pharmacologically acceptable salt thereof, wherein R^(4a) and        R^(5a) are substituents selected from the following substituent        group B2, and R⁶ represents a substituent selected from the        following substituent group A2,    -   Substituent group A2: (1) a hydrogen atom, (2) a C1-C6 alkyl        group, (3) a halogen atom, (4) a cyano group, (5) a C1-C6 alkoxy        group, (6) an amino group wherein a nitrogen atom may be        substituted by a C1-C6 alkyl group, and (7) C1-C6 alkoxy C1-C6        alkyl group,    -   Substituent group B2: (1) a hydrogen atom, (2) a C1-C6 alkyl        group, (3) a halogen atom, (4) a hydroxyl group, (5) a C1-C6        alkoxy group, (6) a C1-C6 alkoxy C1-C6 alkyl group, (7) a C5-C6        cycloalkyl group formed by two C1-C3 alkyl groups attaching to        the same carbon atom, and (8) a tetrahydropyranyl group formed        by two C1-C3 alkyl group attaching to the same carbon atom,        together with an oxygen atom and the above described carbon        atom;    -   6) The compound according to any one of 3) to 5) above or a        pharmacologically acceptable salt thereof, wherein R^(4a) and        R^(5a) represent substituents selected from the following        substituent group B5, and R⁶represents a substituent selected        from the following substituent group A4,    -   Substituent group A4: (1) a hydrogen atom, and (2) a C1-C6        alkoxy group,    -   Substituent group B5: (1) a hydrogen atom, (2) a C1-C6 alkyl        group, (3) a C1-C6 alkoxy C1-C6 alkyl group, (4) a C5-C6        cycloalkyl group formed by two C1-C3 alkyl groups attaching to        the same carbon atom, and (5) a tetrahydropyranyl group formed        by two C1-C3 alkyl group attaching to the same carbon atom,        together with an oxygen atom and the above described carbon        atom;    -   7) The compound according to any one of 3) to 6) above or a        pharmacologically acceptable salt thereof, wherein X_(a)        represents an oxygen atom;    -   8) The compound according to 1) above or a pharmacologically        acceptable salt thereof, which is represented by formula        (I-b-1), formula (I-b-2), formula (I-b-3), or formula (I-b-4):    -   wherein R^(4a) and R^(5a) represent substituents selected from        the following substituent group B5, and R⁶ represents a        substituent selected from the following substituent group A4,    -   Substituent group A4: (1) a hydrogen atom, and (2) a C1-C6        alkoxy group,    -   Substituent group B5: (1) a hydrogen atom, (2) a C1-C6 alkyl        group, (3) a C1-C6 alkoxy C1-C6 alkyl group, (4) a C5-C6        cycloalkyl group formed by two C1-C3 alkyl groups attaching to        the same carbon atom, and (5) a tetrahydropyranyl group formed        by two C1-C3 alkyl group attaching to the same carbon atom,        together with an oxygen atom and the above described carbon        atom;    -   9) The compound according to 3) above or a pharmacologically        acceptable salt thereof, wherein R^(11a) represents a hydroxyl        group, and R^(12a) represents a hydrogen atom or C1-C6 alkyl        group;    -   10) The compound according to 9) above or a pharmacologically        acceptable salt thereof, wherein R^(4a) and R^(5a) are        substituents selected from the following substituent group B2,        and R⁶ represents a substituent selected from the following        substituent group A2,    -   Substituent group A2: (1) a hydrogen atom, (2) a C1-C6 alkyl        group, (3) a halogen atom, (4) a cyano group, (5) a C1-C6 alkoxy        group, (6) an amino group wherein a nitrogen atom may be        substituted by a C1-C6 alkyl group, and (7) C1-C6 alkoxy C1-C6        alkyl group,    -   Substituent group B2: (1) a hydrogen atom, (2) a C1-C6 alkyl        group, (3) a halogen atom, (4) a hydroxyl group, (5) a C1-C6        alkoxy group, (6) a C1-C6 alkoxy C1-C6 alkyl group, (7) a C5-C6        cycloalkyl group formed by two C1-C3 alkyl groups attaching to        the same carbon atom, and (8) a tetrahydropyranyl group formed        by two C1-C3 alkyl group attaching to the same carbon atom,        together with an oxygen atom and the above described carbon        atom;    -   11) The compound according to 9) or 10) above or a        pharmacologically acceptable salt thereof, wherein X_(a)        represents an oxygen atom;    -   12) The compound according to 3) above or a pharmacologically        acceptable salt thereof, wherein R^(11a) and R^(12a) together        form the formula ═N—OR (wherein R^(8c) represents a C1-C6 alkyl        group);    -   13) The compound according to 12) above or a pharmacologically        acceptable salt thereof, wherein R^(4a) and R^(5a) are        substituents selected from the following substituent group B3,        and R⁶ represents a substituent selected from the following        substituent group A2,    -   Substituent group A2: (1) a hydrogen atom, (2) a C1-C6 alkyl        group, (3) a halogen atom, (4) a cyano group, (5) a C1-C6 alkoxy        group, (6) an amino group wherein a nitrogen atom may be        substituted by a C1-C6 alkyl group, and (7) C1-C6 alkoxy C1-C6        alkyl group,    -   Substituent group B3: (1) a hydrogen atom, (2) a C1-C6 alkyl        group, (3) a halogen atom, (4) a hydroxyl group, (5) a C1-C6        alkoxy group, and (6) a C1-C6 alkoxy C1-C6 alkyl group;    -   14) The compound according to 12) or 13) above or a        pharmacologically acceptable salt thereof, wherein X_(a)        represents an oxygen atom;    -   15) The compound according to 1) above or a pharmacologically        acceptable salt thereof, which is represented by formula (I-c-1)        or formula (I-c-2):    -   wherein R³ represents a hydrogen atom or methyl group;    -   and R^(4d), R^(5d), and R⁶ represent substituents selected from        the following substituent group A1,    -   Substituent group Al: (1) a hydrogen atom, (2) a halogen        atom, (3) a cyano group, (4) a hydroxyl group, (5) a nitro        group, (6) a carboxyl group, (7) a C3-C8 cycloalkyl group, (8) a        C2-C6 alkenyl group, (9) a C2-C6 alkynyl group, (10) a C1-C6        alkylthio group, (11) a C1-C6 alkoxycarbonyl group, (12) a C1-C6        alkylsulfonyl group, (13) a C1-C6 alkyl group (wherein the above        described C1-C6 alkyl group may be substituted by 1 to 3        substituents selected from the group consisting of a halogen        atom, a hydroxyl group, and a C1-C6 alkoxy group), (14) a C1-C6        alkoxy group (wherein the above described C1-C6 alkoxy group may        be substituted by 1 to 3 halogen atoms), (15) an amino group        (wherein the above described amino group may be substituted by a        substituent selected from the group consisting of a C1-C6 alkyl        group, a formyl group, a C1-C6 alkanoyl group, and a C1-C6        alkylsulfonyl group), and (16) a carbamoyl group (wherein the        above described carbamoyl group may be substituted by one or two        C1-C6 alkyl groups);    -   16) The compound according to 15) above or a pharmacologically        acceptable salt thereof, wherein R^(4d) and R^(5d) are        substituents selected from the following substituent group B4,        and R⁶ represents a substituent selected from the following        substituent group A2,    -   Substituent group A2: (1) a hydrogen atom, (2) a C1-C6 alkyl        group, (3) a halogen atom, (4) a cyano group, (5) a C1-C6 alkoxy        group, (6) an amino group wherein a nitrogen atom may be        substituted by a C1-C6 alkyl group, and (7) C1-C6 alkoxy C1-C6        alkyl group, Substituent group B4: (1) a hydrogen atom, (2) a        C1-C6 alkyl group, (3) a C1-C6 alkoxy group, and (4) a C1-C6        alkoxy C1-C6 alkyl group;    -   17) The compound according to 1) above or a pharmacologically        acceptable salt thereof, which is represented by formula (I-d-1)        or formula (I-d-2):    -   wherein R³ represents a hydrogen atom or methyl group;    -   R^(4e) and R^(5e) represent substituents selected from the        following substituent group A1; R⁶ represents a substituent        selected from the following substituent group A1; and each of        X_(e) and Y_(e) represents (1) an oxygen atom, (2) a methylene        group, (3) —CONR^(7e)— (wherein R^(7e) represents (1) a hydrogen        atom, or (2) a C1-C6 alkyl group), (4) —NR^(7e)CO— (wherein        R^(7e) has the same above meaning), (5) —NR^(8e)— (wherein        R^(8e) represents (1) a C1-C6 alkyl group, or (2) a C1-C6 acyl        group), or (6) a single bond,    -   Substituent group A1: (1) a hydrogen atom, (2) a halogen        atom, (3) a cyano group, (4) a hydroxyl group, (5) a nitro        group, (6) a carboxyl group, (7) a C3-C8 cycloalkyl group, (8) a        C2-C6 alkenyl group, (9) a C2-C6 alkynyl group, (10) a C1-C6        alkylthio group, (11) a C1-C6 alkoxycarbonyl group, (12) a C1-C6        alkylsulfonyl group, (13) a C1-C6 alkyl group (wherein the above        described C1-C6 alkyl group may be substituted by 1 to 3        substituents selected from the group consisting of a halogen        atom, a hydroxyl group, and a C1-C6 alkoxy group), (14) a C1-C6        alkoxy group (wherein the above described C1-C6 alkoxy group may        be substituted by 1 to 3 halogen atoms), (15) an amino group        (wherein the above described amino group may be substituted by a        substituent selected from the group consisting of a C1-C6 alkyl        group, a formyl group, a C1-C6 alkanoyl group, and a C1-C6        alkylsulfonyl group), and (16) a carbamoyl group (wherein the        above described carbamoyl group may be substituted by one or two        C1-C6 alkyl groups);    -   18) The compound according to 17) above or a pharmacologically        acceptable salt thereof, wherein R^(4e) and R^(5e) are        substituents selected from the following substituent group B3,        and R⁶ represents a substituent selected from the following        substituent group A2,    -   Substituent group A2: (1) a hydrogen atom, (2) a C1-C6 alkyl        group, (3) a halogen atom, (4) a cyano group, (5) a C1-C6 alkoxy        group, (6) an amino group wherein a nitrogen atom may be        substituted by a C1-C6 alkyl group, and (7) C1-C6 alkoxy C1-C6        alkyl group,    -   Substituent group B3: (1) a hydrogen atom, (2) a C1-C6 alkyl        group, (3) a halogen atom, (4) a hydroxyl group, (5) a C1-C6        alkoxy group, and (6) a C1-C6 alkoxy C1-C6 alkyl group;    -   19) The compound according to 1) above or a pharmacologically        acceptable salt thereof, which is represented by formula (I-e-1)        or formula (I-e-2):    -   wherein R³ represents a hydrogen atom or methyl group; R⁶        represents a substituent selected from the following substituent        group A1; R^(7f) represents (1) hydrogen atom, (2) a C1-C6 alkyl        group, (3) a C3-C8 cycloalkyl group, (4) a C2-C6 alkenyl        group, (5) a C2-C6 alkynyl group, or (6) a C1-C6 alkoxy C1-C6        alkyl group; and each of X_(f) and Y_(f) represents (1) a single        bond, (2) a methylene group which may have a substituent        selected from the following substituent group A1, or (3) a        carbonyl group,    -   Substituent group A1: (1) a hydrogen atom, (2) a halogen        atom, (3) a cyano group, (4) a hydroxyl group, (5) a nitro        group, (6) a carboxyl group, (7) a C3-C8 cycloalkyl group, (8) a        C2-C6 alkenyl group, (9) a C2-C6 alkynyl group, (10) a C1-C6        alkylthio group, (11) a C1-C6 alkoxycarbonyl group, (12) a C1-C6        alkylsulfonyl group, (13) a C1-C6 alkyl group (wherein the above        described C1-C6 alkyl group may be substituted by 1 to 3        substituents selected from the group consisting of a halogen        atom, a hydroxyl group, and a C1-C6 alkoxy group), (14) a C1-C6        alkoxy group (wherein the above described C1-C6 alkoxy group may        be substituted by 1 to 3 halogen atoms), (15) an amino group        (wherein the above described amino group may be substituted by a        substituent selected from the group consisting of a C1-C6 alkyl        group, a formyl group, a C1-C6 alkanoyl group, and a C1-C6        alkylsulfonyl group), and (16) a carbamoyl group (wherein the        above described carbamoyl group may be substituted by one or two        C1-C6 alkyl groups);    -   20) The compound according to 19) above or a pharmacologically        acceptable salt thereof, wherein R⁶ represents a substituent        selected from the following substituent group A2; R^(7f)        represents a substituent selected from the following substituent        group B4; and each of X_(f) and Y_(f) represents (1) a single        bond, (2) a methylene group which may have a substituent        selected from the following substituent group B4, or (3) a        carbonyl group,    -   Substituent group A2: (1) a hydrogen atom, (2) a C1-C6 alkyl        group, (3) a halogen atom, (4) a cyano group, (5) a C1-C6 alkoxy        group, (6) an amino group wherein a nitrogen atom may be        substituted by a C1-C6 alkyl group, and (7) C1-C6 alkoxy C1-C6        alkyl group, Substituent group B4: (1) a hydrogen atom, (2) a        C1-C6 alkyl group, and (3) a C1-C6 alkoxy C1-C6 alkyl group;    -   21) The compound according to 1) above or a pharmacologically        acceptable salt thereof, which is represented by formula        (I-f-1), formula (I-f-2), formula (I-f-3), formula (I-f-4),        formula (I-g-1), formula (I-g-2), formula (I-h-1), formula        (I-h-2), formula (I-h-3), or formula (I-h-4):    -   wherein R³ represents a hydrogen atom or methyl group;    -   and R⁶ and R^(7g) represent substituents selected from the        following substituent group A1 (excluding a hydroxyl group for        R^(7g)),    -   Substituent group Al: (1) a hydrogen atom, (2) a halogen        atom, (3) a cyano group, (4) a hydroxyl group, (5) a nitro        group, (6) a carboxyl group, (7) a C3-C8 cycloalkyl group, (8) a        C2-C6 alkenyl group, (9) a C2-C6 alkynyl group, (10) a C1-C6        alkylthio group, (11) a C1-C6 alkoxycarbonyl group, (12) a C1-C6        alkylsulfonyl group, (13) a C1-C6 alkyl group (wherein the above        described C1-C6 alkyl group may be substituted by 1 to 3        substituents selected from the group consisting of a halogen        atom, a hydroxyl group, and a C1-C6 alkoxy group), (14) a C1-C6        alkoxy group (wherein the above described C1-C6 alkoxy group may        be substituted by 1 to 3 halogen atoms), (15) an amino group        (wherein the above described amino group may be substituted by a        substituent selected from the group consisting of a C1-C6 alkyl        group, a formyl group, a C1-C6 alkanoyl group, and a C1-C6        alkylsulfonyl group), and (16) a carbamoyl group (wherein the        above described carbamoyl group may be substituted by one or two        C1-C6 alkyl groups);    -   22) The compound according to 21) above or a pharmacologically        acceptable salt thereof, wherein R⁶ represents a substituent        selected from the following substituent group A2, and R^(7g)        represents a substituent selected from the following substituent        group A3,    -   Substituent group A2: (1) a hydrogen atom, (2) a C1-C6 alkyl        group, (3) a halogen atom, (4) a cyano group, (5) a C1-C6 alkoxy        group, (6) an amino group wherein a nitrogen atom may be        substituted by a C1-C6 alkyl group, and (7) C1-C6 alkoxy C1-C6        alkyl group,    -   Substituent group A3: (1) a hydrogen atom, (2) a C1-C6 alkyl        group, (3) a halogen atom, (4) a cyano group, and (5) a C1-C6        alkoxy C1-C6 alkyl group;    -   23) The compound according to 21) or 22) above or a        pharmacologically acceptable salt thereof, wherein R⁶ represents        a substituent selected from the following substituent group A4,        and R^(7g) represents a substituent selected from the following        substituent group B6,    -   Substituent group A4: (1) a hydrogen atom, and (2) a C1-C6        alkoxy group,    -   Substituent group B6: (1) a hydrogen atom, and (2) a C1-C6 alkyl        group;    -   24) The compound according to 1) above or a pharmacologically        acceptable salt thereof, which is represented by formula (I-i-1)        or formula (I-i-2):    -   wherein R3 represents a hydrogen atom or methyl group;    -   and R⁶, R^(9h), and R^(10h) represent substituents selected from        the following substituent group A1; and X_(h) and Y_(h)        represent (1) a methine group or (2) a nitrogen atom,        Substituent group A1: (1) a hydrogen atom, (2) a halogen        atom, (3) a cyano group, (4) a hydroxyl group, (5) a nitro        group, (6) a carboxyl group, (7) a C3-C8 cycloalkyl group, (8) a        C2-C6 alkenyl group, (9) a C2-C6 alkynyl group, (10) a C1-C6        alkylthio group, (11) a C1-C6 alkoxycarbonyl group, (12) a C1-C6        alkylsulfonyl group, (13) a C1-C6 alkyl group (wherein the above        described C1-C6 alkyl group may be substituted by 1 to 3        substituents selected from the group consisting of a halogen        atom, a hydroxyl group, and a C1-C6 alkoxy group), (14) a C1-C6        alkoxy group (wherein the above described C1-C6 alkoxy group may        be substituted by 1 to 3 halogen atoms), (15) an amino group        (wherein the above described amino group may be substituted by a        substituent selected from the group consisting of a C1-C6 alkyl        group, a formyl group, a C1-C6 alkanoyl group, and a C1-C6        alkylsulfonyl group), and (16) a carbamoyl group (wherein the        above described carbamoyl group may be substituted by one or two        C1-C6 alkyl groups);    -   25) The compound according to 24) above or a pharmacologically        acceptable salt thereof, wherein R^(9h), R^(10h), R⁶ represent        substituents selected from the following substituent group A2;        and X_(h) and Y_(h) represent (1) a methine group or (2) a        nitrogen atom,    -   Substituent group A2: (1) a hydrogen atom, (2) a C1-C6 alkyl        group, (3) a halogen atom, (4) a cyano group, (5) a C1-C6 alkoxy        group, (6) an amino group wherein a nitrogen atom may be        substituted by a C1-C6 alkyl group, and (7) C1-C6 alkoxy C1-C6        alkyl group; 26) The compound according to 8)-25), wherein R⁶        represents a hydrogen atom;    -   27) The compound according to 1) above selected from the        following group or a pharmacologically acceptable salt thereof:    -   1)        1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide,    -   2)        1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,    -   3)        1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-6-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,    -   4)        1-{l-[2-(6-Methoxy-3-oxoindan-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,    -   5)        1-{1-[2-(6-Methoxy-2-methylbenzoxazol-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,    -   6)        1-{1-[2-(6-Methoxy-2-methylbenzoxazol-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,    -   7)        1-{1-[2-(6-Methoxy-3-methylbenzo[d]isoxazol-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,    -   8)        1-{1-[2-(6-Methoxy-3-methylbenzo[d]isoxazol-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,    -   9)        1-{1-[2-(5-Methoxy-l-oxoindan-4-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,        and    -   10)        1-{1-[2-(7-Methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide;    -   28) The compound according to 1) above selected from the        following group or a pharmacologically acceptable salt thereof:    -   1)        1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide,    -   2)        1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,        and    -   3)        1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-6-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide;    -   29) A pharmaceutical composition comprising, as an active        ingredient, a compound represented by the following formula (I)        or a pharmacologically acceptable salt thereof:    -   wherein R¹ and R² are substituents adjacent to each other, and        together with two carbon atoms to each of which they attach,        form:    -   (1) a 5- to 7-membered non-aromatic carbocyclic group,    -   (2) a 5- to 7-membered non-aromatic heterocyclyl group,    -   (3) a 6-membered aromatic carbocyclic group, or    -   (4) a 5- or 6-membered aromatic heterocyclyl group, which may be        substituted by 1 to 4 substituents selected from the following        substituent group B1;    -   R³ represents a hydrogen atom or methyl group; and    -   R⁶ represents a substituent selected from the following        substituent group A1,    -   Substituent group A1: (1) a hydrogen atom, (2) a halogen        atom, (3) a cyano group, (4) a hydroxyl group, (5) a nitro        group, (6) a carboxyl group, (7) a C3-C8 cycloalkyl group, (8) a        C2-C6 alkenyl group, (9) a C2-C6 alkynyl group, (10) a C1-C6        alkylthio group, (11) a C1-C6 alkoxycarbonyl group, (12) a C1-C6        alkylsulfonyl group, (13) a C1-C6 alkyl group (wherein the above        described C1-C6 alkyl group may be substituted by 1 to 3        substituents selected from the group consisting of a halogen        atom, a hydroxyl group, and a C1-C6 alkoxy group), (14) a C1-C6        alkoxy group (wherein the above described C1-C6 alkoxy group may        be substituted by 1 to 3 halogen atoms), (15) an amino group        (wherein the above described amino group may be substituted by a        substituent selected from the group consisting of a C1-C6 alkyl        group, a formyl group, a C1-C6 alkanoyl group, and a C1-C6        alkylsulfonyl group), and (16) a carbamoyl group (wherein the        above described carbamoyl group may be substituted by one or two        C1-C6 alkyl groups),    -   Substituent group B1: (1) a hydrogen atom, (2) a halogen        atom, (3) a cyano group, (4) a hydroxyl group, (5) a nitro        group, (6) an oxo group, (7) a carboxyl group, (8) a C3-C8        cycloalkyl group, (9) a C2-C6 alkenyl group, (10) a C2-C6        alkynyl group, (11) a C1-C6 alkylthio group, (12) a C1-C6        alkoxycarbonyl group, (13) a C1-C6 alkylsulfonyl group, (14) a        C1-C6 alkyl group (wherein the above described C1-C6 alkyl group        may be substituted by a halogen atom, a hydroxyl group, and a        C1-C6 alkoxy group), (15) a C1-C6 alkoxy group (wherein the        above described C1-C6 alkoxy group may be substituted by 1 to 3        halogen atoms), (16) an amino group (wherein the above described        amino group may be substituted by a substituent selected from        the group consisting of a C1-C6 alkyl group, a formyl group, a        C1-C6 alkanoyl group, and a C1-C6 alkylsulfonyl group),    -   (17) a carbamoyl group (wherein the above described carbamoyl        group may be substituted by one or two C1-C6 alkyl groups), (18)        a C1-C6 alkoxyimino group, (19) a C5-C6 cycloalkyl group formed        by two C1-C3 alkyl groups attaching to the same carbon atom,        and (20) a tetrahydropyranyl group formed by two C1-C3 alkyl        group attaching to the same carbon atom, together with an oxygen        atom and the above described carbon atom;    -   30) The pharmaceutical composition according to 28) above        characterized in that it is an agent for treating or preventing        lower urinary tract symptoms;    -   31) The pharmaceutical composition according to 30) above        characterized in that it is an agent for treating or preventing        symptoms regarding urinary storage;    -   32) The pharmaceutical composition according to 30) or 31) above        characterized in that it is an agent for treating or preventing        increased urinary frequency or urinary incontinence;    -   33) The pharmaceutical composition according to 29) above        characterized in that it is an agent for treating or preventing        cognitive impairment which are associated with Alzheimer's        disease or senile dementia;, learning or memory disorder, or        anxiety disorder,    -   34) The pharmaceutical composition according to 29) above        characterized in that it is an agent for treating or preventing        schizophrenia, emotional disorder, alcohol and/or cocaine        dependence, symptoms associated with withdrawal from nicotine        ingestion or smoking, or visual attention disorder; and    -   35) The pharmaceutical composition according to 29) above        characterized in that it is an agent for treating or preventing        sleep disorder, migraine, temperature instability, eating        disorder, vomiting, gastrointestinal disorder, or genital        insufficiency. The compound represented by formula (I) of the        present invention, a pharmacologically acceptable salt thereof,        and an agent for treating or preventing lower urinary tract        symptoms, which has ability to bind to a serotonin 1A receptor,        are all novel inventions that have not been described in any        publications.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a powder X-ray diffraction pattern of the A-type crystalobtained in Example 70. The horizontal axis indicates a diffractionangle (2θ), and the vertical axis indicates peak strength;

FIG. 2 shows a powder X-ray diffraction pattern of the B-type crystalobtained in Example 71. The horizontal axis indicates a diffractionangle (2θ), and the vertical axis indicates peak strength;

FIG. 3 shows a powder X-ray diffraction pattern of the C-type crystalobtained in Example 71. The horizontal axis indicates a diffractionangle (2θ), and the vertical axis indicates peak strength; and

FIG. 4 shows a powder X-ray diffraction pattern of the D-type crystalobtained in Example 72. The horizontal axis indicates a diffractionangle (2θ), and the vertical axis indicates peak strength.

DETAILED DESCRIPTION OF THE INVENTION

The meanings of symbols or terms used in the specification of thepresent application will be explained below, and the present inventionwill be described in detail.

In addition, it is to be noted that, as a matter of convenience, thestructural formula of a compound indicates a fixed isomer in thespecification of the present application. However, the present inventionincludes all of geometrical isomers to occur in the structure ofcompounds, isomers such as optical isomers on the basis of asymmetriccarbon, stereoisomers, tautomers and isomeric mixtures. Thus, thepresent invention is not limited by the structural formula shown as amatter of convenience in the present specification, but either an isomeror a mixture may be included. Hence, it is likely that a compound has anasymmetric carbon atom in a molecule thereof, and that an opticallyactive substance and racemete exist. In the present invention, there areno limitation regarding such cases, and both cases are included in thescope of the present invention. Moreover, there is the case where acrystal polymorphism exists. This case is also not limited, and it maybe either single crystal form or those mixtures likewise, and it may behydrate besides anhydride.

In the specification of the present application, the term “lower urinarytract symptoms” is used as a generic name for symptoms relating todisorder in urine collection mechanism and disorder in urinationmechanism.

In the specification of the present application, the term “urinarydysfunction” is used to mean various types of “disorder/abnormality”impairing normal urination, including (1) “abnormality of the volume ofurine” such as polyuria, oliguria, or anuria, (2) “abnormality of thefrequency of urination” such as increased urinary frequency oroligakisuria, (3) “difficulty in urination”, (4) “anuresis”, (5)“urinary incontinence”, (6) “abnormality of urination condition” such asenuresis, (7) “abnormality of urinary stream” such as decreased urinarystream, decreased urinary force, interruption, or double voiding, andthe like. In addition, the term “urinary dysfunction” also includesdiseases specified in the form of subordinate conception, with respectto the “disorders/abnormalities” described in (1) to (7) above that arespecified in the form of super-ordinate conception. For example,“urinary dysfunction” naturally includes the following diseases:neuropathic bladder, neurotic increased urinary frequency, unstablebladder, increased urinary frequency associated with a bladderirritation state caused by chronic bladder, increased urinary frequencyassociated with a bladder irritation state caused by chronicprostatitis, urinary urgency, urge incontinence, reflex urinaryincontinence, stress incontinence, overflow incontinence, urinaryincontinence associated with a bladder irritation state caused bychronic cystitis, urinary incontinence associated with a bladderirritation state caused by chronic prostatitis, nocturia, psychogenicdysuria, nocturnal enuresis, or the like.

In the specification of the present application, the term “anxietydisorder” is used to mean, for example, generalized anxiety disorder,panic disorder, phobic neurosis (e.g. agoraphobia, anthropophobia,simple phobia), obsessive-compulsive disorder, or the like. The term“emotional disorder” is used herein to mean depression (majordepression), manic-depressive psychosis (bipolar disorder), dysthymia(depressive neurosis), or the like.

Each of “a 5- to 7-membered non-aromatic carbocyclic group,” “a 5- to7-membered non-aromatic heterocyclyl group,” “a 6-membered aromaticcarbocyclic group,” and “a 5- or 6-membered aromatic heterocyclyl group”that are contained in the agent of the present invention for treating orpreventing lower urinary tract symptoms, represented by the abovedescribed formula (I), has the following meaning.

The term “5- to 7-membered non-aromatic carbocyclic group” means anon-aromatic hydrocarbon group containing 5 to 7 carbon atoms. Examplesof such a group may include a cyclopentyl group, a cyclohexyl group, anda cycloheptyl group.

The term “5- to 7-membered non-aromatic heterocyclyl group” means anon-aromatic heterocyclyl group containing 1 to 4 heteroatoms. Preferredexamples of such a group may include a pyrrolidinyl group, animidazolidinyl group, a pyrazolidinyl group, a piperidinyl group, apiperazinyl group, a morpholinyl group, a tetrahydropyranyl group, adioxanyl group, a piperidin-2-oxo yl group, a dihydro-[1,3]oxazin-2-oxoyl group, a [1,4]oxazepan-5-oxo yl group, adihydro-[1,3]oxazin-2,4-dioxo yl group, a 5,6-dihydro-1H-pyridin-2-oxoyl group, a tetrahydropyran-4-oxo yl group, a 2,3-dihydropyran-4-oxo ylgroup, a tetrahydropyran-4-hydroxy yl group, an oxepan-4-oxo yl group, a1,3-oxazolidin-2-oxo yl group and the like.

The term “6-membered aromatic carbocyclic group” means a phenyl group.

A preferred example of the “5- or 6-membered aromatic heterocyclylgroup” may be (1) nitrogen containing heteroaromatic groups such as apyrrolyl group, a pyridyl group, a pyridaziniyl group, a pyrimidinylgroup, a pyrazinyl group; (2) sulfur containing heteroaromatic groupssuch as a thienyl group; (3) oxygen containing heteroaromatic groupssuch as a furyl group, a oxaspiro[5,4]decanyl group; (4) two or moreheteroatoms containing heteroaromatic groups such as a thiazoyl group,an isothiazolyl group, an oxazoyl group, an isoxazolyl group, and thosetwo or more heteroatoms are selected from a nitrogen atom, an oxygenatom, and a sulfur atom.

In formula (I), each of substituent group A1, substituent group A2,substituent group A3, substituent group A4, substituent group B1,substituent group B2, substituent group B3, substituent group B4,substituent group B5, substituent group B6, and substituent group B7,includes the following groups.

Substituent group Al consists of (1) a hydrogen atom, (2) a halogenatom, (3) a cyano group, (4) a hydroxyl group, (5) a nitro group, (6) acarboxyl group, (7) a C3-C8 cycloalkyl group, (8) a C2-C6 alkenyl group,(9) a C2-C6 alkynyl group, (10) a C1-C6 alkylthio group, (11) a C1-C6alkoxycarbonyl group, (12) a C1-C6 alkylsulfonyl group, (13) a C1-C6alkyl group (wherein the above described C1-C6 alkyl group may besubstituted by 1 to 3 substituents selected from the group consisting ofa halogen atom, a hydroxyl group, and a C1-C6 alkoxy group), (14) aC1-C6 alkoxy group (wherein the above described C1-C6 alkoxy group maybe substituted by 1 to 3 halogen atoms), (15) an amino group (whereinthe above described amino group may be substituted by a substituentselected from the group consisting of a C1-C6 alkyl group, a formylgroup, a C1-C6 alkanoyl group, and a C1-C6 alkylsulfonyl group), (16) acarbamoyl group (wherein the above described carbamoyl group may besubstituted by one or two C1-C6 alkyl groups), and (17) a C1-C6alkoxyimino group.

Substituent group A2 consists of (1) a hydrogen atom, (2) a C1-C6 alkylgroup, (3) a halogen atom, (4) a cyano group, (5) a C1-C6 alkoxy group,(6) an amino group wherein a nitrogen atom may be substituted by a C1-C6alkyl group, and (7) C1-C6 alkoxy C1-C6 alkyl group.

Substituent group A3 consists of (1) a hydrogen atom, (2) a C1-C6 alkylgroup, (3) a halogen atom, (4) a cyano group, and (5) a C1-C6 alkoxyC1-C6 alkyl group.

Substituent group A4 consists of (1) a hydrogen atom and (2) a C1-C6alkoxy group.

Substituent group B1 consists of (1) a hydrogen atom, (2) a halogenatom, (3) a cyano group, (4) a hydroxyl group, (5) a nitro group, (6) anoxo group, (7) a carboxyl group, (8) a C3-C8 cycloalkyl group, (9) aC2-C6 alkenyl group, (10) a C2-C6 alkynyl group, (11) a C1-C6 alkylthiogroup, (12) a C1-C6 alkoxycarbonyl group, (13) a C1-C6 alkylsulfonylgroup, (14) a C1-C6 alkyl group (wherein the above described C1-C6 alkylgroup may be substituted by a halogen atom, a hydroxyl group, and aC1-C6 alkoxy group), (15) a C1-C6 alkoxy group (wherein the abovedescribed C1-C6 alkoxy group may be substituted by 1 to 3 halogenatoms), (16) an amino group (wherein the above described amino group maybe substituted by a substituent selected from the group consisting of aC1-C6 alkyl group, a formyl group, a C1-C6 alkanoyl group, and a C1-C6alkylsulfonyl group), (17) a carbamoyl group (wherein the abovedescribed carbamoyl group may be substituted by one or two C1-C6 alkylgroups), (18) a C1-C6 alkoxyimino group, (19) a C5-C6 cycloalkyl groupformed by two C1-C3 alkyl groups attaching to the same carbon atom, and(20) a tetrahydropyranyl group formed by two C1-C3 alkyl group attachingto the same carbon atom, together with an oxygen atom and the abovedescribed carbon atom.

When the substituents described in (19) or (20) above are specificallyillustrated, they are represented by the following formula, for example:

Substituent group B2 consists of (1) a hydrogen atom, (2) a C1-C6 alkylgroup, (3) a halogen atom, (4) a hydroxyl group, (5) a C1-C6 alkoxygroup, (6) a C1-C6 alkoxy C1-C6 alkyl group, (7) a C5-C6 cycloalkylgroup formed by two C1-C3 alkyl groups attaching to the same carbonatom, and (8) a tetrahydropyranyl group formed by two C1-C3 alkyl groupattaching to the same carbon atom, together with an oxygen atom and theabove described carbon atom.

Substituent group B3 consists of (1) a hydrogen atom, (2) a C1-C6 alkylgroup, (3) a halogen atom, (4) a hydroxyl group, (5) a C1-C6 alkoxygroup, and (6) a C1-C6 alkoxy C1-C6 alkyl group.

Substituent group B4 consists of (1) a hydrogen atom, (2) a C1-C6 alkylgroup, (3) a C1-C6 alkoxy group, and (4) a C1-C6 alkoxy C1-C6 alkylgroup.

Substituent group B5 consists of (1) a hydrogen atom, (2) a C1-C6 alkylgroup, (3) a C1-C6 alkoxy C1-C6 alkyl group, (4) a C5-C6 cycloalkylgroup formed by two C1-C3 alkyl groups attaching to the same carbonatom, and (5) a tetrahydropyranyl group formed by two C1-C3 alkyl groupattaching to the same carbon atom, together with an oxygen atom and theabove described carbon atom.

Substituent group B6 consists of (1) a hydrogen atom and (2) a C1-C6alkyl group.

Substituent group B7 consists of (1) a hydrogen atom, (2) a C1-C6 alkylgroup, (3) a halogen atom, (4) a cyano group, and (5) a C1-C6 alkoxyC1-C6 alkyl group.

The term “halogen atom” means a fluorine atom, chlorine atom, bromineatom, iodine atom. It is preferably a fluorine atom, chlorine atom, orbromine atom.

The term “C1-C6 alkyl group” means an alkyl group containing 1 to 6carbon atoms. Preferred examples of such a group include linear orbranched alkyl groups such as a methyl group, ethyl group, n-propylgroup, isopropyl group, n-butyl group, isobutyl group, tert-butyl group,n-pentyl group, isopentyl group, neopentyl group, n-hexyl group,1-methylpropyl group, 1,2-dimethylpropyl group, 2-ethylpropyl group,1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl group,1,1,2-trimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group,1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 2-ethylbutyl group,1,3-dimethylbutyl group, 2-methylpentyl group, or 3-methylpentyl group.

The term “C2-C6 alkenyl group” means an alkenyl group containing 2 to 6carbon atoms. Preferred examples of such a group include linear orbranched alkenyl groups such as a vinyl group, allyl group, 1-propenylgroup, isopropenyl group, 1-buten-1-yl group, 1-buten-2-yl group,1-buten-3-yl group, 2-buten-1-yl group, or 2-buten-2-yl group.

The term “C2-C6 alkynyl group” means an alkynyl group containing 2 to 6carbon atoms. Preferred examples of such a group include linear orbranched alkynyl groups such as an ethynyl group, 1-propynyl group,2-propynyl group, butynyl group, pentynyl group, or hexynyl group.

The term “C3-C8 cycloalkyl group” means a cyclic alkyl group containing3 to 8 carbon atoms. Preferred examples of such a group include acyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexylgroup, cycloheptyl group, and cyclooctyl group.

The term “C1-C6 alkoxy group” means an alkyl group containing 1 to 6carbon atoms, wherein a hydrogen atom is substituted by an oxygen atom.Preferred examples of such a group include a methoxy group, an ethoxygroup, a n-propoxy group, an isopropoxy group, a sec-propoxy group, an-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxygroup, a n-pentyloxy group, an isopentyloxy group, a sec-pentyloxygroup, a tert-pentyloxy group, a n-hexyloxy group, an isohexyloxy group,a 1,2-dimethylpropoxy group, a 2-ethylpropoxy group, a1-methyl-2-ethylpropoxy group, a 1-ethyl-2-methylpropoxy group, a1,1,2-trimethylpropoxy group, a 1,1-dimethylbutoxy group, a2,2-dimethylbutoxy group, a 2-ethylbutoxy group, a 1,3-dimethylbutoxygroup, a 2-methylpentyloxy group, a 3-methylpentyloxy group, a hexyloxygroup, and the like.

The term “C1-C6 alkylthio group” means an alkyl group containing 1 to 6carbon atoms, wherein a hydrogen atom is substituted by a sulfur atom.Preferred examples of such a group include a methylthio group, anethylthio group, a n-propylthio group, an isopropylthio group, an-butylthio group, an isobutylthio group, a tert-butylthio group, an-pentylthio group, an isopentylthio group, a neopentylthio group, an-hexylthio group, a 1-methylpropylthio group, and the like.

The term “C1-C6 alkoxycarbonyl group” means a group formed by binding acarbonyl group to the aforementioned alkoxy group. Preferred examples ofsuch a group include a methoxycarbonyl group and an ethoxycarbonylgroup.

The term “C5-C6 cycloalkyl group formed by two C1-C3 alkyl groupsattaching to the same carbon atom” means a cyclopentyl group orcyclohexyl group.

The term “C1-C6 alkanoyl group (C1-C6 alkylcarbonyl group)” means analkyl group containing 1 to 6 carbon atoms wherein a hydrogen atom issubstituted by a carbonyl group. Preferred examples of such a groupinclude an acetyl group, a propionyl group, and a butyryl group, and thelike.

The term “C1-C6 alkylsulfonyl group” means an alkyl group containing 1to 6 carbon atoms wherein a hydrogen atom is substituted by a sulfonylgroup. Preferred examples of such a group include a methanesulfonylgroup, an ethanesulfonyl group, and the like.

The term “amino group that may be substituted by a C1-C6 alkyl group”means an amino group to which an alkyl group containing 1 to 6 carbonatoms attaches. Preferred examples of such a group include an aminogroup, a methylamino group, an ethylamino group, a propylamino group,and the like.

Examples of an “amino group that may be substituted by a formyl group”include an amino group and a formylamino group.

The term “amino group that may be substituted by a C1-C6 alkanoyl group”means an amino group to which an alkanoyl group containing 1 to 6 carbonatoms attaches. Preferred examples of such a group include anacetylamino group, a propionylamino group, a butyrylamino group, and thelike.

The term “amino group that may be substituted by a C1-C6 alkylsulfonylgroup” means an amino group to which an alkylsulfonyl group containing 1to 6 carbon atoms attaches. Preferred examples of such a group includean amino group, a methanesulfonylamino group, an ethanesulfonylaminogroup, an n-propanesulfonylamino group, an n-butanesulfonylamino group,an N-methylmethanesulfonylamino group, and the like.

The term “carbamoyl group that may be substituted by one or two C1-C6alkyl groups” means a carbamoyl group wherein one or two hydrogen atomsmay be mono- or di-substituted by C1-C6 alkyl group(s). Preferredexamples of such a group include an N-methylcarbamoyl group, anN,N-dimethylcarbamoyl group, an N-ethylcarbamoyl group, anN,N-diethylcarbamoyl group, and the like.

The term “C1-C6 alkoxyimino group” means an imino group wherein ahydrogen atom is substituted by a C1-C6 alkoxy group. Preferred examplesof such a group include a methoxyimino group, an ethoxyimino group, andthe like.

Next, the compound represented by formula (I) of the present inventionwill be described.

The compound represented by formula (I) selectively binds to a serotonin1A receptor and has an antagonism to the receptor. It is used to treator prevent diseases in which a serotonin 1A receptor is involved, suchas lower urinary tract symptoms. Preferred examples of such a compoundmay include the compound represented by formula (I-a-1), the compoundrepresented by formula (I-a-2), the compound represented by formula(I-a-3), the compound represented by formula (I-a-4), the compoundrepresented by formula (I-c-1), the compound represented by formula(I-c-2), the compound represented by formula (I-d-1), the compoundrepresented by formula (I-d-2), the compound represented by formula(I-e-1), the compound represented by formula (I-e-2), the compoundrepresented by formula (I-f-1), the compound represented by formula(I-f-2), the compound represented by formula (I-f-3), the compoundrepresented by formula (I-f-4), the compound represented by formula(I-g-1), the compound represented by formula (I-g-2), the compoundrepresented by formula (I-h-1), the compound represented by formula(I-h-2), the compound represented by formula (I-h-3), the compoundrepresented by formula (I-h-4), the compound represented by formula(I-i-1), and the compound represented by formula (I-i-2).

Among these compounds, as the compound represented by formula (I-a-1),(I-a-2), (I-a-3), or (I-a-4), a compound wherein, in each formula,

-   -   R^(11a) and R^(12a) form a carbonyl group, together with carbon        atoms to which R^(11a) and R^(12a) attach,    -   X_(a) represents an oxygen atom,    -   R³ represents a hydrogen atom or methyl group,    -   R^(4a) and R^(5a) represent substituents selected from the group        consisting of (1) a hydrogen atom, (2) a C1-C6 alkyl group, (3)        a C1-C6 alkoxy C1-C6 alkyl group, (4) a C5-C6 cycloalkyl group        formed by two C1-C3 alkyl groups attaching to the same carbon        atom, and (5) a tetrahydropyranyl group formed by two C1-C3        alkyl group attaching to the same carbon atom, together with an        oxygen atom and the above described carbon atom,    -   R⁶ represents a substituent selected from the group consisting        of (1) a hydrogen atom and (2) a C1-C6 alkoxy group, and    -   Na represents an integer between 1 and 3,    -   or a pharmacologically acceptable salt thereof, is more        preferable.

As the compound represented by formula (I-c-1) or (I-c-2), a compoundwherein, in each formula,

-   -   R³represents a hydrogen atom or methyl group,    -   R^(4d) and R^(5d) are substituents selected from the group        consisting of (1) a hydrogen atom, (2) a C1-C6 alkyl group, (3)        a C1-C6 alkoxy group, and (4) a C1-C6 alkoxy C1-C6 alkyl group,        and    -   R⁶ represents a substituent selected from the group consisting        of (1) a hydrogen atom, (2) a C1-C6 alkyl group, (3) a halogen        atom, (4) a cyano group, (5) a C1-C6 alkoxy group, (6) an amino        group wherein a nitrogen atom may be substituted by a C1-C6        alkyl group, and (7) a C1-C6 alkoxy C1-C6 alkyl group,    -   or a pharmacologically acceptable salt thereof, is more        preferable.

As the compound represented by formula (I-d-1) or (I-d-2), a compoundwherein, in each formula,

-   -   R³represents a hydrogen atom or methyl group,    -   each of X_(e) and Y_(e) represents (1) an oxygen atom, (2) a        methylene group, (3) —CONR^(7e)— (wherein R^(7e) represents (1)        a hydrogen atom, or (2) a C1-C6 alkyl group), (4) —NR^(7e)CO—        (wherein R^(7e) has the same above meaning), (5) —NR^(8e) —        (wherein R^(8e) represents (1) a C1-C6 alkyl group, or    -   (2) a C1-C6 acyl group), or (6) a single bond,    -   R^(4e) and R^(5e) represent substituents selected from the group        consisting of (1) a hydrogen atom, (2) a C1-C6 alkyl group, (3)        a halogen atom, (4) a hydroxyl group,    -   (5) a C1-C6 alkoxy group, and (6) a C1-C6 alkoxy C1-C6 alkyl        group, and    -   R⁶ represents a substituent selected from the group consisting        of (1) a hydrogen atom, (2) a C1-C6 alkyl group, (3) a halogen        atom, (4) a cyano group, (5) a C1-C6 alkoxy group, (6) an amino        group wherein a nitrogen atom may be substituted by a C1-C6        alkyl group, and (7) a C1-C6 alkoxy C1-C6 alkyl group,    -   or a pharmacologically acceptable salt thereof, is more        preferable.

As the compound represented by formula (I-e-1) or (I-e-2), a compoundwherein, in each formula,

-   -   R³represents a hydrogen atom or methyl group,    -   R⁶ represents a substituent selected from the group consisting        of (1) a hydrogen atom, (2) a C1-C6 alkyl group, (3) a halogen        atom, (4) a cyano group, (5) a C1-C6 alkoxy group, (6) an amino        group wherein a nitrogen atom may be substituted by a C1-C6        alkyl group, and (7) a C1-C6 alkoxy C1-C6 alkyl group,    -   R^(7f) represents a substituent selected from the group        consisting of (1) a hydrogen atom, (2) a C1-C6 alkyl group,        and (3) a C1-C6 alkoxy C1-C6 alkyl group, and each of X_(f) and        Y_(f) represents substituents selected from the group consisting        of (1) a single bond, (2) a methylene group that may have a        substituent selected from the group consisting of a hydrogen        atom, a C1-C6 alkyl group, and a C1-C6 alkoxy C1-C6 alkyl group,        and (3) a carbonyl group,    -   or a pharmacologically acceptable salt thereof, is more        preferable.

As the compound represented by formula (I-f-1), (I-f-2) (I-f-3),(I-f-4), (I-g-1), (I-g-2), (I-h-1), (I-h-2), (I-h-3), or (I-h-4), acompound wherein, in each formula,

-   -   R³represents a hydrogen atom or methyl group,    -   R⁶ represents a substituent selected from the group consisting        of (1) a hydrogen atom, (2) a C1-C6 alkyl group, (3) a halogen        atom, (4) a cyano group, (5) a C1-C6 alkoxy group, (6) an amino        group wherein a nitrogen atom may be substituted by a C1-C6        alkyl group, and (7) a C1-C6 alkoxy C1-C6 alkyl group, and    -   R^(7g) represents a substituent selected from the group        consisting of (1) a hydrogen atom, (2) a C1-C6 alkyl group, (3)        a halogen atom, (4) a cyano group, and (5) C1-C6 alkoxy C1-C6        alkyl group,    -   or a pharmacologically acceptable salt thereof, is more        preferable.

As the compound represented by formula (I-i-1) or (I-i-2), a compoundwherein, in each formula,

-   -   R³represents a hydrogen atom or methyl group,    -   R^(9h), R^(10h), and R⁶ represent substituents selected from the        group consisting of (1) a hydrogen atom, (2) a C1-C6 alkyl        group, (3) a halogen atom, (4) a cyano group, (5) a C1-C6 alkoxy        group, (6) an amino group wherein a nitrogen atom may be        substituted by a C1-C6 alkyl group, and (7) a C1-C6 alkoxy C1-C6        alkyl group, and each of X_(h) and Y_(h) represents (1) a        methine group or (2) a nitrogen atom,    -   or a pharmacologically acceptable salt thereof, is more        preferable.

Among these compound groups, the most preferred compounds are asfollows. In the case of the compound represented by formula (I-b-1),(I-b-2), (I-b-3), or (I-b-4), a compound wherein, in each formula, R³represents a hydrogen atom or methyl group, R^(4a) and R^(5a) representsubstituents selected from the group consisting of (1) a hydrogen atom,(2) a C1-C6 alkyl group, (3) a C1-C6 alkoxy C1-C6 alkyl group, (4) aC5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attaching to thesame carbon atom, and (5) a tetrahydropyranyl group formed by two C1-C3alkyl group attaching to the same carbon atom, together with an oxygenatom and the above described carbon atom, and R⁶ represents asubstituent selected from the group consisting of (1) a hydrogen atomand (2) a C1-C6 alkoxy group or a pharmacologically acceptable saltthereof, is most preferable. In the case of the compound represented byformula (I-f-1), (I-f-2), (I-f-3), (I-f-4), (I-g-1), (I-g-2), (I-h-1),(I-h-2), (I-h-3), or (I-h-4), a compound wherein, in each formula, R³represents a hydrogen atom or methyl group, R⁶ represents a substituentselected from the group consisting of (1) a hydrogen atom and (2) aC1-C6 alkoxy group, and R^(7g) represents a substituent selected fromthe group consisting of (1) a hydrogen atom and (2) a C1-C6 alkyl groupor a pharmacologically acceptable salt thereof, is most preferable.

In particular, compounds selected from the following group orpharmacologically acceptable salts thereof are preferable:

-   -   1)        1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide,    -   2)        1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,    -   3)        1-{l-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-6-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,    -   4)        1-{l-[2-(6-Methoxy-3-oxoindan-5-yl)ethyl]piperidin-4-yl)-1H-indole-6-carboxamide,    -   5)        1-{1-[2-(6-Methoxy-2-methylbenzoxazol-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,    -   6)        1-{1-[2-(6-Methoxy-2-methylbenzoxazol-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,    -   7)        1-{1-[2-(6-Methoxy-3-methylbenzo[d]isoxazol-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,    -   8)        1-{1-[2-(6-Methoxy-3-methylbenzo[d]isoxazol-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,    -   9)        1-{1-[2-(5-Methoxy-1-oxoindan-4-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,        and    -   10)        1-{1-[2-(7-Methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide.

Among them, for example,

-   -   1)        1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide,    -   2)        1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,        and    -   3)        1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-6-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide.

These compounds or pharmacologically acceptable salts thereof have agood antagonism to a 5-HT1A receptor, and are useful as agents fortreating or preventing lower urinary tract symptoms, and particularly,symptoms regarding urinary storage.

Preferred embodiments of the above described compound represented byformula (I) are described above. However, the active ingredients of thepharmaceutical of the present invention are not limited to specificcompounds described in the present specification. All of embodimentsincluded in the scope of the compound represented by formula (I) can beselected to the maximum extent possible.

A method for producing the compound represented by formula (I) of thepresent invention will be described below.

A compound represented by the general formula (I):

wherein R¹, R², R³, and R⁶ have the same meanings as described above, issynthesized by the general production methods 1 to 5 described below,for example. The term “room temperature” described below is used to meana temperature approximately between 15° C. and 30° C.[General Production Method 1)

wherein R₍₁₎ represents a lower alkyl group such as a methyl group orethyl group, a lower aralkyl group such as a benzyl group, or the like;R₍₂₎ represents a hydrogen atom, a methyl group, or the like; Xrepresents a leaving group including a halogen atom (a chlorine atom, abromine atom, an iodine atom, etc.), a sulfonyloxy group such as amethanesulfonyloxy group, p-toluenesulfonyloxy group, ortrifluoromethanesulfonyloxy group, or the like; R₍₁₃₎ represents amethyl group, an ethyl group, or the like, which are capable of beinghydrolyzed; P₍₁₎ represents a protecting group for an amino group, whichis able to be deprotected, such as a benzyloxycarbonyl group,tert-butyloxycarbonyl group, or the like; and R¹, R², R³, and R⁶ havethe same meanings as described above.

The above described [General production method 1] is a method forproducing the compound represented by formula (I) of the presentinvention, which uses compound (1-1) as a raw material and conductsmulti-stage steps ranging from [Step 1-1] to [Step 1-7].

Compound (1-1) can also be produced from a commercially availableproduct according to the methods known to persons skilled in the art.Examples of such known methods may include: Coe, J. W.; Vetelino, M. G.;Bradlee, M. J.; Tetrahedron Lett., 37 (34), 6045-6048 (1996), Arai, E.;Tokuyama, H.; Linsell, M. S.; Fukuyama, T.; Tetrahedron Lett., 39 (1),71-74 (1998), Tishler, A. N., Lanza, T. J.; Tetrahedron Lett., 27 (15),1653 (1986), and Sakamoto Takao, Kondo Yoshinori, Yamanaka Hiroshi,Chem. Pharm. Bull., Vol. 34, P. 2362 (1986).

With regard to compound (1-2) and compound (1-6), commercially availableproducts may directly be used, or these compounds may also be producedfrom commercially available products according to methods known topersons skilled in the art. Compound (1-9) and compound (1-10) may beproduced from commercially available products according to methods knownto persons skilled in the art, or may also be produced by the methoddescribed in production examples in the present examples.

[Step 1-1]

This is a step of obtaining compound (1-3) by the reductive amination ofcompound (1-1) and compound (1-2).

The reaction can be carried out under the same conditions as thosecommonly used for the reductive amination of a carbonyl compound and anamine compound. The reduction reaction in this step is not particularlylimited. Examples of such a reaction may include a reductive aminationreaction using a reducing agent such as borane or a boron hydridecomplex compound, and a catalytic reduction reaction using a metalcatalyst under a hydrogen atmosphere.

Examples of a reductive amination reaction using a boron hydride complexcompound may be methods described in publications such as W. S. Emerson,Organic Reactions, 4, 174 (1948), C. F. Lane, Synthesis, 135. (1975), J.C. Ctowell and S. J. Pedegimas, Synthesis, 127 (1974), A. F.Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryanoff and R. D. Shah,Journal of Organic Chemistry, 61, 3849 (1996).

Examples of a boron hydride complex compound used herein may includesodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride.

When a boron hydride complex compound is used as a reducing agent, asolvent is not particularly limited, as long as it does not inhibit thereaction and dissolves a starting substance to a certain extent.Specific examples of a solvent used herein may include methanol,ethanol, tetrahydrofuran, N,N-dimethylformamide, methylene chloride, and1,2-dichloroethane. When the present reaction is carried out in thecoexistence of acid, preferred results such as the improvement of yieldcan be obtained. Acid is not particularly limited. Preferred examples ofsuch acid may include mineral acids such as hydrochloric acid, organicacids such as acetic acid, and Lewis acids such as zinc chloride, aboron trifluoride diethyl ether complex, or titanium (IV)tetraisopropoxide.

Compound (1-2) is used at a ratio of 0.8 to 2.5 equivalents, andpreferably 1 to 1.5 equivalents, with respect to compound (1-1). A boronhydride complex compound is used at a ratio of 1 to 3 equivalents, andpreferably 1 to 1.5 equivalents, with respect to compound (1-1). Thereaction time is not particularly limited. It is generally between 0.5and 48 hours, and preferably between 0.5 and 12 hours.

The reaction temperature is not particularly limited. It is generallybetween −78° C. and a solvent-reflux temperature, and preferably betweena temperature on ice and a room temperature.

When a catalytic reduction reaction is carried out under a hydrogenatmosphere, a solvent used is not particularly limited, as long as itdoes not inhibit the reaction. Examples of a solvent may includemethanol, ethanol, tetrahydrofuran, and 1,4-dioxane. Examples of a metalcatalyst used for the reaction may include palladium, platinum oxide,and Raney nickel. The reaction time is not particularly limited. It isgenerally between 1 and 48 hours, and preferably between 1 and 24 hours.

The reaction conditions are not particularly limited. The reaction canbe carried out at a temperature between a room temperature and asolvent-reflux temperature at a pressure between an ordinary pressureand a pressure of 150 atmospheres, and preferably at a temperaturebetween a room temperature and 60° C. at a pressure between an ordinarypressure and a pressure of 5 atmospheres.

[Step 1-2]

This step involves a method of obtaining compound (1-4) by the ringclosure of compound (1-3) with acid.

The reaction can be carried out under the same reaction conditions asthose described in, for example, Coe, J. W.; Vetelino, M. G.; Bradlee,M. J.; Tetrahedron Lett., 37 (34), 6045-6048 (1996), Arai, E.; Tokuyama,H.; Linsell, M. S.; Fukuyama, T.; Tetrahedron Lett., 39 (1), 71-74(1998), Tishler, A. N., Lanza, T. J.; Tetrahedron Lett., 27 (15), 1653(1986), and Sakamoto Takao, Kondo Yoshinori, Yamanaka Hiroshi, Chem.Pharm. Bull., Vol. 34, P. 2362 (1986).

A solvent used in the present reaction is not particularly limited, aslong as it does not inhibit the reaction and dissolves a startingsubstance to a certain extent. Examples of such a solvent may include:water; mixed solvent consisting of water and an organic solvent such asmethanol, ethanol, tetrahydrofuran, 1,4-dioxane, benzene, or toluene;and organic solvents such as methanol, ethanol, tetrahydrofuran,1,4-dioxane, benzene, or toluene. The present reaction can be carriedout by allowing appropriate acid at a ratio between 1 equivalent and anexcessive amount to acting on the aforementioned compound in theaforementioned solvent. Examples of acid used herein may include aceticacid, hydrogen chloride, hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, trifluoroacetic acid, p-toluenesulfonic acid,p-toluenesulfonic acid-pyridinium salt, and camphorsulfonic acid.

The reaction time is not particularly limited. It is generally between 1and 24 hours, and preferably between 1 and 4 hours.

The reaction temperature is generally between a temperature on ice and asolvent-reflux temperature.

It is to be noted that [Step 1-1] and [Step 1-2] can also be carried outby one-pot reaction without isolating compound (1-3).

[Step 1-3]

This is a step of obtaining compound (1-5) by alkaline hydrolysis ofcompound (1-4).

The reaction can be carried-out under the same reaction conditions asthose described in, for example, Matassa, V. G.; Brown, F. J.;Bernstein, P. R.; Shapiro, H. S.; Maduskuie, T. P. J.; Cronk, L. A.;Vacek, E. P.; Yee, Y. K.; Snyder, D. W.; Krell, R. D.; Lerman, C. L.;Maloney, J. J.; J. Med. Chem., 33 (9), 2621-2629 (1990).

Specifically, for example, a base such as sodium hydroxide is added to asolution containing compound (1-4). The mixture is then stirred forseveral hours to 1 day. Thereafter, the resultant mixture is treatedwith acid such as citric acid, so as to obtain compound (1-5).

A solvent used in the present reaction is not particularly limited, aslong as it does not inhibit the reaction and dissolves a startingsubstance to a certain extent. Examples of such a solvent may includemethanol, ethanol, 2-propanol, tetrahydrofuran, and 1,4-dioxane. A baseused herein is not particularly limited. Preferred examples of such abase may include sodium hydroxide, potassium hydroxide, and lithiumhydroxide. The amount of a base used is between 1 equivalent and anexcessive amount, and preferably between 1 and 20 equivalents, withrespect to compound (1-4).

The reaction time is not particularly limited. It is generally between 1and 24 hours, and preferably between 1 and 6 hours.

The reaction temperature is not particularly limited. It is generallybetween a room temperature and a solvent-reflux temperature.

When an ester is a benzyl ester or allyl ester, carboxylic acid can beobtained under the same conditions as those generally used for thedeprotection of a protecting group for a carboxylic acid compound (whichare conditions described in publications such as T. W. Green and P. G.M. Wuts, “Protective groups in Organic Chemistry, Second Edition”, JohnWiley & Sons (1991), pp. 248-251).

[Step 1-4]

This is a step of obtaining compound (1-7) by condensing compound (1-5)and compound (1-6) with a condensing agent.

The condensation reaction of compound (1-5) and (1-6) with a condensingagent can be carried out under the same conditions as commonly usedconditions described in the following publications. Such known methodsinclude Rosowsky, A.; Forsch, R. A.; Moran, R. G.; Freisheim, J. H.; J.Med. Chem., 34 (1), 227-234 (1991), Brzostwska,. M.; Brossi, A.;Flippen-Anderson, J. L.; Heterocycles, 32 (10), 1969-1972 (1991),Romero, D. L.; Morge, R., A.; Biles, C.; Berrios-Pena, N.; May, P. D.;Palmer, J. R.; Johnson, P. D.; Smith, H. W.; Busso, M.; Tan, C.-K.;Voorman, R. L.; Reusser, F.; Althaus, I. W.; Downey, K. M.; So, A. G.;Resnick, L.; Tarpley, W. G., Aristoff, P. A.; J. Med. Chem., 37 (7),999-1014 (1994).

Compound (1-6) may be either a free form or a salt.

A solvent used in the present reaction is not particularly limited, aslong as it does not inhibit“the reaction. Examples of such a solvent mayinclude tetrahydrofuran, 1,4-dioxane, ethyl acetate, methyl acetate,methylene chloride, chloroform, N,N-dimethylformamide, toluene, andxylene. Examples of a condensing agent may include CDI(N,N′-carbonyldiimidazole), Bop(1H-1,2,3-benzotriazol-1-yloxy(tri(dimethylamino))phosphoniumhexafluorophosphate), WSC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride), DCC (N,N-dicyclohexylcarbodiimide), anddiethylphosphoryl cyanide. Compound (1-6) is used at a ratio between 1equivalent and an excessive amount with respect to compound (1-5). Inaddition, an organic base such as triethylamine may also be added at aratio between 1 equivalent and an excessive amount, as necessary.

The reaction time is not particularly limited. It is generally between0.5 and 48 hours, and preferably between 0.5 and 24 hours.

The reaction temperature is not particularly limited, and is differentdepending on a raw material used, a solvent used, and the like. It ispreferably between a temperature on ice and a solvent-refluxtemperature.

Moreover, compound (1-7) can also be produced from compound (1-5) andcompound (1-6) according to alternative methods described in (1) and (2)below.

Alternative Method (1)

Compound (1-5) is converted into a mixed acid anhydride. Then, the mixedacid anhydride is allowed to react with compound (1-6), so as to obtaincompound (1-7). Such a mixed acid anhydride can be synthesized by meansknown to persons skilled in the art. For example, compound (1-5) isallowed to react with a chloroformic ester such as ethyl chloroformatein the presence of a base such as triethylamine. Such a chloroformicester and a base are used at a ratio between 1 and 2 equivalents withrespect to compound (1-5). The reaction temperature is between −30° C.and a room temperature, and preferably between −20° C. and a roomtemperature.

A step of condensing a mixed acid anhydride and compound (1-6) iscarried out, for example, by allowing the mixed acid anhydride to reactwith compound (1-6) in a solvent such as methylene chloride,tetrahydrofuran, or N,N-dimethylformamide. Compound (1-6) is used at aratio between 1 equivalent and an excessive amount with respect to themixed acid anhydride.

The reaction time is not particularly limited. It is generally between0.5 and 48 hours, and preferably between 0.5 and 12 hours.

The reaction temperature is between −20° C. and 50° C., and preferablybetween −20° C. and a room temperature.

Alternative Method (2)

Compound (1-5) is converted into an activated ester. Then, the activatedester is allowed to react with compound (1-6), so as to obtain compound(1-7). A step of obtaining such an activated ester can be carried out byallowing compound (1-5) to react with an activated ester-synthesizingreagent in a solvent such as 1,4-dioxane, tetrahydrofuran, orN,N-dimethylformamide, in the presence of a condensing agent such asDCC. N-hydroxysuccinimide is an example of such an activatedester-synthesizing reagent. Such an activated ester-synthesizing reagentand a condensing agent are used at a ratio between 1 and 1.5 equivalentswith respect to compound (1-5). The reaction time is not particularlylimited. It is generally between 0.5 and 48 hours, and preferablybetween 0.5 and 24 hours.

The reaction temperature is between −20° C. and 50° C., and preferablybetween −20° C. and a room temperature.

A step of condensing an activated ester and compound (1-6) is carriedout by allowing the activated ester to react with compound (1-6) in asolvent such as methylene chloride, tetrahydrofuran, orN,N-dimethylformamide. Compound (1-6) is used at a ratio between 1equivalent and an excessive amount with respect to the activated ester.

The reaction time is not particularly limited. It is generally between0.5 and 48 hours, and preferably between 0.5 and 24 hours.

The reaction temperature is between −20° C. and 500C, and preferablybetween −20° C. and a room temperature.

[Step 1-4′]

This is a step of obtaining compound (1-7) by condensing compound (1-4)and compound (1-6).

This condensation reaction can be carried out under the same conditionsas those commonly used for the condensation reaction of an estercompound and an amine compound. Known methods include Dodd, J. H.; Guan,J.; Schwender, C. F.; Synth. Commun., 23 (7), 1003-1008 (1993), Sim, T.B.; Yoon, N. M.; and Synlett, (10), 827-828 (1994). An amine compound(1-6) used may be either a free form or a salt.

A solvent used in the present reaction is not particularly limited, aslong as it does not inhibit the reaction. Examples of such a solvent mayinclude. methanol, ethanol, 1-propanol, 2-propanol, 1-butanol,tetrahydrofuran, 1,4-dioxane, toluene, xylene, and acetic acid. Inaddition, it is also possible to use an amine compound (1-6) as asolvent. Compound (1-6) is used at a ratio between 1 equivalent and anexcessive amount with respect to compound (1-4).

The reaction time is not particularly limited. It is generally between 1and 48 hours, and preferably between 1 and 24 hours.

The reaction temperature is not particularly limited, and is differentdepending on a raw material used, a solvent used, and the like. It ispreferably between a room temperature and a solvent-reflux temperature.

Moreover, in the present reaction, acids such as p-toluenesulfonic acidor camphorsulfonic acid, Lewis acids such as trimethylaluminum, or basessuch as sodium hydride may be added to the reaction, thereby obtaininggood results such as the reduction of the reaction time or theimprovement of yield. Furthermore, a well-closed heat-resistingcontainer such as an autoclave may be used to heat a reaction mixture toa high temperature between 100° C. and 250° C., thereby obtaining goodresults such as the reduction of the reaction time.

[Step. 1-5]

This is a step of obtaining compound (1-8) by deprotecting a protectinggroup for the secondary amine of compound (1-7).

The deprotection reaction can be carried out under the same conditionsas those commonly used for the deprotection of a protecting group for anamino compound. Such conditions are described in publications such as T.W. Green and P. G. M. Wuts, “Protective groups in Organic Chemistry,Second Edition”, John Wiley & Sons (1991), pp. 309-405. When the aminogroup of compound (1-7) is protected by a benzyloxycarbonyl group, forexample, the protecting group is deprotected by hydrogenolysis ofcompound (1-7) using palladium on carbon as a catalyst in a solvent suchas alcohol, so as to obtain compound (1-8).

[Step 1-6]

This is a step of obtaining a compound represented by general formula(I) by the reductive amination of compound (1-8) and compound (1-9).

In this step, compound (1-8) and compound (1-9) are used as rawmaterials, and the method described in the aforementioned productionmethod ([Step 1-1]) is applied, so as to synthesize the compoundrepresented by general formula (I). In addition, a commerciallyavailable product may directly be used as compound (1-9), or the abovecompound may also be produced from a commercially available product by amethod known to persons skilled in the art. Moreover, it can also beproduced by production examples in the present examples, or the methoddescribed in the [General production method A, B, C, D, or E] section.Furthermore, the used compound (1-8) may be either a free form or asalt.

[Step 1-7]

This is a step of obtaining a compound represented by general formula(I) by the nucleophilic substitution reaction of compound (1-8) andcompound (1-10).

This nucleophilic substitution reaction can be carried out under thesame conditions as those commonly used for the reaction of a secondaryamine with a halogen compound (for example, conditions described inHirai, Y.; Terada, T.; Okaji, Y.; Yamazaki, T.; Tetrahedron Lett., 31(33), 4755-4758 (1990), etc.). In addition, a commercially availableproduct may directly be used as compound (1-10), or the above compoundmay also be produced from a commercially available product by a methodknown to persons skilled in the art. Moreover, it can also be producedby production examples in the present examples, or the method describedin the [General production method E] section. Furthermore, the usedcompound (1-8) may be either a free form or a salt.

A solvent used in the reaction is not particularly limited, as long asit does not inhibit the reaction and dissolves a starting substance to acertain extent. Preferred examples of such a solvent may includemethanol, ethanol, propanol, tetrahydrofuran, benzene, toluene, xylene,acetonitrile, methylene chloride, chloroform, N,N-dimethylformamide, anddimethyl sulfoxide. Compound (1-10) is used at a ratio between 1 and 10equivalents, and preferably between 1 and 5 equivalents, with respect tocompound (1-8).

The reaction time is not particularly limited. It is generally between 1and 72 hours, and preferably between 1 and 48 hours.

The reaction temperature is generally between a room temperature and asolvent-reflux temperature, and preferably between a room temperatureand 100° C.

Moreover, addition of a base may provide good results such as theimprovement of yield. A base used is not particularly limited, as longas it does not inhibit the reaction. Preferred examples of such a basemay include sodium carbonate, potassium carbonate, sodium hydroxide,potassium hydroxide, diazabicycloundecen, sodium hydride, potassiumhydride, sodium methoxide, potassium methoxide, potassium tert-butoxide,triethylamine, and diisopropylethylamine.

The compound represented by general formula (I) can also be produced bythe following [General production method 1′].[General Production Method 1′]

wherein R₍₂₎, R¹, R², R⁶, and P₍₁₎ have the same meanings as describedabove; and X represents a leaving group, such as a halogen atom (achlorine atom, bromine atom, iodine atom, or the like) or a sulfonyloxygroup such as a methanesulfonyloxy group, p-toluenesulfonyloxy group, ortrifluoromethanesulfonyloxy group.

The above described [General production method 1′] is a method forproducing the compound represented by general formula (I) of the presentinvention, which comprises multi-stage steps ranging from [Step 1′-1] to[Step 1′-9].

A commercially available product may directly be used as compound(1′-1), or the compound may be produced from a commercially availableproduct according to a method known to persons skilled in the art. Inaddition, commercially available products may directly be used ascompound (1-2) and compound (1-6), or these compounds may be producedfrom commercially available products according to methods known topersons skilled in the art.

[Step 1′-1]

This is a step of synthesizing compound (1′-2) by using compound (1′-1)and compound (1-6) as raw materials and applying the method described inthe aforementioned production method ([Step 1-4]).

[Step 1′-2] to [Step 1′-4]

This is a step of producing compound (1′-6) from compound (1′-2) by thecombined use of various reactions that have been known to personsskilled in the art.

Examples of such a known method may include: Coe, J. W.; Vetelino, M.G.; Bradlee, M. J.; Tetrahedron Lett., 37 (34), 6045-6048 (1996), Arai,E.; Tokuyama, H.; Linsell, M. S.; Fukuyama,. T.; Tetrahedron Lett., 39(1), 71-74 (1998), Tishler, A. N., Lanza, T. J.; Tetrahedron Lett., 27(15), 1653 (1986), and Sakamoto Takao, Kondo Yoshinori, YamanakaHiroshi, Chem. Pharm. Bull., Vol. 34, P. 2362 (1986).

Specifically, compound (1′-6) can be produced by performing stepsranging from [Step 1′-2] to [Step 1′-4]. Needless to say, the method forproducing compound (1′-6) is not limited to these steps. Compound (1′-6)can also be produced by methods described in the aforementionedpublications.

[Step 1′-2]

This is a step of obtaining compound (1′-4) from compound (1′-2) andcompound (1′-3).

A method for producing an enamine derivative of compound (1′-4) from anitrotoluene derivative of compound (1′-2) is a synthesis method knownto persons skilled in the art. The reaction can be carried out under thesame conditions as those described in, for example, Coe, J. W.;Vetelino, M. G.; Bradlee, M. J.; Tetrahedron Lett., 37 (34), 6045-6048(1996).

[Step 1′-3]

This is a step of obtaining compound (1′-5) from compound (1′-4).

A method for producing an acetal derivative of compound (1′-5) from anenamine derivative of compound (1′-4) is a synthesis method known topersons skilled in the art. The reaction can be carried out under thesame conditions as those described in Coe, J. W.; Vetelino, M. G.;Bradlee, M. J.; Tetrahedron Lett., 37 (34), 6045-6048 (1996); etc.

[Step. 1′-4]

This is a step of obtaining compound (1′-6) from compound (1′-5).

A method for synthesizing an aniline compound of compound (1′-6) byreducing a nitro compound of compound (1′-5) is a synthesis method knownto persons skilled in the art. An example of such a method may be areduction by catalytic hydrogenation using a precious metal catalystsuch as Raney nickel, palladium, ruthenium, or rhodium. In this case,means for using palladium or palladium hydroxide is preferable.Otherwise, a reduction reaction using iron under neutral conditionswhere ammonium chloride is used, is also preferable.

[Step 1′-5]

This is a step of synthesizing compound (1′-7) by using compound (1′-6)and compound (1-2) as raw materials and applying the method described inthe above production method ([Step 1-1]).

[Step 1′-6]

This is a step of synthesizing compound (1-7) by using compound (1′-7)as a raw material and applying the method described in the aboveproduction method ([Step 1-2]).

[Step 1′-7]

This is a step of synthesizing-compound (1-8) by using compound (1-7) asa raw material and applying the method described in the above productionmethod ([Step 1-5]).

[Step 1′-8]

This is a step of synthesizing the compound represented by generalformula (I) by using compound (1-8) and compound (1-9) as raw materialsand applying the method described in the above production method ([Step1-6]).

[Step 1′-9]

This is a step of synthesizing the compound represented by generalformula (I) by using compound (1-8) and compound (1-10) as raw materialsand applying the method described in the above production method ([Step1-7]).[General Production Method 2]

wherein R₍₂₎ has the same meaning as described above; and R₍₉₎represents C₆H (R¹) (R²) (R⁶) (OMe)-(CH₂)₂—.

Compound (1-1) can be produced from a commercially available productaccording to a method known to persons skilled in the art. Examples ofsuch a method may include: Coe, J. W.; Vetelino, M. G.; Bradlee, M. J.;Tetrahedron Lett., 37 (34), 6045-6048 (1996), Arai, E.; Tokuyama, H.;Linsell, M. S.; Fukuyama, T.; Tetrahedron Lett., 39 (1), 71-74 (1998),Tishler, A. N., Lanza, T. J.; Tetrahedron Lett., 27 (15), 1653 (1986),and Sakamoto Takao, Kondo Yoshinori, Yamanaka Hiroshi, Chem. Pharm.Bull., Vol. 34, P. 2362 (1986).

In addition, a commercially available product may directly be used ascompound (2-1), or the above compound may also be produced from acommercially available product by a method known to persons skilled inthe art. Moreover, it can also be produced by the method described inthe [General production method F] section.

[Step 2-1]

This is a step of synthesizing compound (2-2) by conducting thereductive amination reaction of compound (1-1) and compound (2-1)according to the method described in the above production method ([Step1-1]).

[Step 2-2]

This is a step of synthesizing compound (2-3) by using compound (2-2) asa raw material and applying the method described in the above productionmethod ([Step 1-2]).

[Step 2-3]

This is a step of synthesizing compound (2-4) by using compound (2-3) asa raw material and applying the method described in the above productionmethod ([Step 1-3]).

[Step 2-4]

This is a step of synthesizing the compound represented by generalformula (I) by using compound (2-4) as a raw material and applying themethod described in the above production method ([Step 1-4]). Acommercially available product may directly be used as compound (1-6),or the above compound may also be produced from a commercially availableproduct according to a method known to persons skilled in the art.

[Step 2-5]

This is a step of synthesizing the compound represented by generalformula (I) by using compound (2-3) as a raw material and applying themethod described in the above production method ([Step 1-4]).

The compound represented by general formula (I) can also be produced bythe following [General production method 2′].[General Production Method 2′]

wherein R₍₂₎, R₍₉₎, and R₍₁₃₎ have the same meanings as described above.

This is a step of producing the compound represented by general formula(I) of the present invention, which uses compound (1′-6) as a rawmaterial and performs [Step 2′-1] and [Step 2′-2]. Compound (1′-6) canbe produced from a commercially available product according to a methodknown to persons skilled in the art. Compound (2-1) can be produced froma commercially available product according to a method known to personsskilled in the art. Further, it can also be produced by the methoddescribed in [General production method F] that will be described later.

(Step 2′-1]

This is a step of synthesizing compound (2′-1) by using compound (1′-6)and compound (2-1) as raw materials and applying the method described inthe above production-method (Step 1-1).

[Step 2′-2]

This is a step of synthesizing the compound represented by generalformula (I) by using compound (2′-1) as a raw material and applying themethod described in the above production method ([Step 1-2]).[General Production Method 3]

wherein R₍₂₎ and R₍₉₎ have the same meanings as described above; Zrepresents OR₍₁₎ (wherein R₍₁₎ has the same meaning as described above)or R₍₂₎HN.[Step 3-1]

Compound (3-2) can be synthesized by using compound (3-1) and compound(2-1) as raw materials and applying the method described in the aboveproduction method ([Step 1-1]).

[Step 3-2]

This is a step of obtaining compound (3-3) by the cyclization ofcompound (3-2). A method for synthesizing indole by the cyclization ofan acetylene compound (3-2) has been known to persons skilled in theart. The reaction can be carried out under the same conditions as thosedescribed in, for example, Fujiwara Junya, Fukutani Yoshimi, SanoHiromi, Maruoka Keiji, Yamamoto Hisashi, J. Am. Chem. Soc., Vol. 105, P.7177 (1983); and Ezquerra, J.; Pedregal, C.; Lamas, C.; Barluenga, J.;Perez, M.; Garcia-Martin, M. A.; Gonzalez, J. M.; J. Org. Chem., 61(17), 5804-5812 (1996).

[Step 3-3]

This is a step of synthesizing compound (3-4) by using compound (3-3)and applying the method described in the above production method ([Step2-3]). In a case where compound (3-3) has already had an appropriatesubstituent, however, this step can be omitted.

[Step 3-4]

This is a step of synthesizing the compound represented by generalformula (I) by using compound (3-4) as a raw material and applying themethod described in the above production method ([Step 1-4]). In a casewhere compound (3-3) has already had an appropriate substituent,however, this step can be omitted. Compound (3-1) used in a generalproduction method can be synthesized by [General production method G].[General Production Method 4]

wherein R₍₁₎, R₍₂₎, R₍₉₎, and X have the same meanings as describedabove; and D represents a carboxyl group or a group capable of beingmodified to a carboxyl group.

Compound (4-1) can be produced by a method known to persons skilled inthe art. The compound can be synthesized under the same conditions asthose described in, for example, Quallich, G. J.; Morrissey, P. M.;Synthesis, (1), 51-53 (1993), Urban, F. J.; Breitenbach, R.; Gonyaw, D.;Synth. Commun., 26 (8), 1629-1638 (1996), Zhu, J.; Beugelmans, R.;Bourdent, S.; Chastanet, J.; Roussi, G.; J. Org. Chem., 60 (20),6389-6396 (1995).

[Step 4-1]

This is a step of obtaining an amino compound (4-2) by subjecting anitro compound (4-1) to a reduction reaction.

The reduction of a nitro group is a reaction known to persons skilled inthe art. An example of such a reduction may be catalytic hydrogenationusing a precious metal catalyst such as Raney nickel, palladium,palladium hydroxide, ruthenium, rhodium, or platinum. Another examplemay be means for using iron, tin, or zinc under neutral or acidicconditions.

[Step 4-2]

This is a step of synthesizing compound (4-3) by using compound (4-2) asa raw material and applying the method described in the above productionmethod ([Step 1-1]).

[Step 4-3]

This is a step of obtaining compound (4-4) by the halogenation ofcompound (4-3).

The reaction can be carried out under the same conditions as thosedescribed in, for example, Chan, F.; Magnus, P.; Mciver, E. G.;Tetrahedron Lett., 41 (6), 835-838 (2000)., Owa, T.; Okauchi, T.;Yoshimatsu, K.; Sugi, N.; Ozawa, Y.; Nagasu, T.; Koyanagi, N.; Okabe,T.; Kitoh, K.; Yoshino, H.; Bioorg. Med. Chem. Lett., 10 (11),1223-1226-(2000)., Kubo. A., Nakai. T., Synthesis, 365 (1980).

Specifically, for example, a solution containing compound (4-3) isheated together with phosphorus oxychloride or the like, so as to obtaincompound (4-4).

A solvent used in the reaction is not particularly limited, as long asit does not inhibit the reaction and dissolves a starting substance to acertain extent. Preferred examples of such a solvent may includeacetonitrile and toluene. In addition, phosphorus oxychloride may alsobe used as a solvent. Such phosphorus oxychloride is used at a ratiobetween 1 equivalent and an excessive amount with respect to a rawmaterial.

The reaction temperature is generally between a temperature on ice and asolvent-reflux temperature, and more preferably between a roomtemperature and a solvent-reflux temperature.

The reaction time is not particularly limited. It is generally between0.2 and 48 hours, and preferably between 0.2 and 24 hours.

Moreover, there may be cases where good results such as the improvementof yield can be obtained by addition of a base. A base used herein isnot particularly limited, as long as it does not inhibit the reaction.Preferred examples of such a base may include triethylamine, pyridine,and diisopropylethylamine.

[Step 4-4]

This is a step of obtaining compound (4-5) by the dehalogenationreaction of compound (4-4).

This reaction can be carried out under the same conditions as those usedfor the known dehalogenation reaction of an aromatic ring. The reactioncan be carried out under the same conditions as those described in, forexample, Candiani, I.; Debernardinis, S.; Cabri, W.; Marchi, M.;Bedeschi, A.; Penco, S.; Synlett, (4), 269-270 (1993)., Tanaka, A.; Ito,K.; Nishino, S.; Motoyama, Y.; Takasugi, H.; Chem. Pharm. Bull., 42 (3),560-569 (1994).

Specifically, compound (4-5) can be obtained by the hydrogenation of asolution containing compound (4-4) in the presence of a metal catalyst.

A solvent used in a catalytic reduction reaction in a hydrogenatmosphere is not particularly limited, as long as it does not inhibitthe reaction. Examples of such a solvent may include methanol, ethanol,tetrahydrofuran, and 1,4-dioxane. Examples of a metal catalyst used inthe reaction may include palladium, platinum oxide, and Raney nickel.The reaction conditions are not particularly limited. The reaction canbe carried out at a temperature between a room temperature and asolvent-reflux temperature at a pressure between an ordinary pressureand a pressure of 150 atmospheres, and preferably at a temperaturebetween a room temperature and 60° C. at a pressure between an ordinarypressure and a pressure of 5 atmospheres. The reaction time is notparticularly limited. It is generally between 0.5 and 48 hours, andpreferably between 0.5 and 24 hours.

[Step 4-5]

This is a step of obtaining the compound represented by general formula(I) by the conversion of a substituent D in compound (4-5).

Conversion of compound (4-5) into the compound represented by generalformula (I) can be conducted by a general method known to personsskilled in the art. When the substituent D is an alkoxycarbonyl groupfor example, the compound represented by general formula (I) can besynthesized by applying the methods described in [Step 1-3] and [Step1-4] or [Step 1-4′].[General Production Method 5]

wherein R₍₂₎ and R₍₉₎ have the same meanings as described above; andR′₍₂₎ and R′₍₉₎ represent R₍₂₎ and R₍₉₎, respectively, which areappropriately modified. [General production method 5] is a method forproducing a compound represented by general formula (I)′ from thecompound represented by general formula (I) as a raw material. (Thecompound represented by general formula (I)′ is included in the compoundrepresented by general formula (I).)

The compound represented by general formula (I) can be produced by theabove described [General production method 1] or the like.

[Step 5-1]

This is a step of obtaining the compound represented by general formula(I)′ by modification of R₍₂₎ or R₍₉₎ in the compound represented bygeneral formula (I).

Modification of R₍₂₎ and R₍₉₎ can be carried out by performing variousreactions known to persons skilled in the art, or by the combined use ofvarious reactions. In addition, the compound represented by generalformula (I)′ can also be produced by methods described in productionexamples in the present examples.

Next, a method for producing main raw material compounds used-in theinvention of the present application will be described. First, compound(1-9) used in [General production method 1] and [General productionmethod 1′] will be described. Compound [1-9] can be produced by [Generalproduction method A] to [General production method E] and [Generalproduction method H]. The final compounds produced by these productionmethods may sometimes be indicated by different formulas to explain eachstep. However, all these compounds correspond to compound (1-9).[General Production Method A] (Synthesis Method of compound (1-9))

wherein ring A represents (1) a bicyclic group formed by condensation ofa benzene ring and a 5- to 7-membered non-aromatic carbocyclic group,(2) a bicyclic group formed by-condensation of a benzene ring and a 5-to 7-membered non-aromatic heterocyclyl group, (3) a bicyclic groupformed by condensation of a benzene ring and a 6-membered aromaticcarbocyclic group, (4) a bicyclic group formed by condensation of abenzene ring and a 5- or 6-membered aromatic heterocyclyl group, or abenzene ring capable of being converted into (1) to (4) above; each ofR₍₄₎, R₍₅₎, and R₍₆₎ represents a substituent necessary for syntheticmodification as appropriate, such as a C1-C6 alkanoyl group, ahydroxymethyl group that may be protected by a TBDMS group or the like,or a C1-C6 alkoxy group that may be substituted by a C1-C6alkoxycarbonyl group, as well as a substituent selected from thefollowing substituent group B1, and R′₍₄₎, R″₍₄₎, R′₍₅₎, R″₍₅₎,R′_((6), R″) ₍₆₎ represent those formed by appropriately modifying R₍₄₎,R₍₅₎, and R₍₆₎, wherein each of R₍₄₎, R₍₅₎, R₍₆₎, R′₍₄₎, R′₍₅₎, R′₍₆₎,R″₍₄₎, R″₍₅₎, and R″₍₆₎ represents a substituent existing on ring A; andL₍₁₎ is a leaving group and represents a halogen atom (a chlorine atom,bromine atom, or iodine atom) or a sulfonyloxy group such as amethanesulfonyloxy group, p-toluenesulfonyloxy group, ortrifluoromethanesulfonyloxy group,

-   -   Substituent group B1: (1) a hydrogen atom, (2) a halogen        atom, (3) a cyano group, (4) a hydroxyl group, (5) a nitro        group, (6) an oxo group, (7) a carboxyl group, (8) a C3-C8        cycloalkyl group, (9) a C2-C6 alkenyl group, (10) a C2-C6        alkynyl group, (11) a C1-C6 alkylthio group, (12) a C1-C6        alkoxycarbonyl group, (13) a C1-C6 alkylsulfonyl group, (14) a        C1-C6 alkyl group (wherein the above described C1-C6 alkyl group        may be substituted by a halogen atom, a hydroxyl group, and a        C1-C6 alkoxy group), (15) a C1-C6 alkoxy group (wherein the        above described C1-C6 alkoxy group may be substituted by 1 to 3        halogen atoms), (16) an amino group (wherein the above described        amino group may be substituted by a substituent selected from        the group consisting of a C1-C6 alkyl group, a formyl group, a        C1-C6 alkanoyl group, and a C1-C6 alkylsulfonyl group), (17) a        carbamoyl group (wherein the above described carbamoyl group may        be substituted by one or two C1-C6 alkyl groups), (18) a C1-C6        alkoxyimino group, (19) a C5-C6 cycloalkyl group formed by two        C1-C3 alkyl groups attaching to a single carbon atom, and (20) a        tetrahydropyranyl group-formed by two C1-C3 alkyl groups        attaching to a single carbon atom, together with an oxygen atom        and the above described carbon atom.

A commercially available product may directly be used as compound (a-1),or the above compound may also be produced from a commercially availableproduct by a method known to persons skilled in the art. Moreover, itcan also be produced by production examples in the present examples.

[Step A-1]

This is a step of obtaining compound (a-3) by the allylation reaction ofcompound (a-1) with compound (a-2).

This reaction can be carried out under the same conditions as those usedin the allylation reaction of allyl halide with a phenol derivative(including a heterocyclic ring) (which are conditions described in, forexample, Nichols, D. E.; Snyder, S. E.; Oberlender, R.; Johnson, M. P.;Huang, X.; J. Med. Chem., 34 (1), 276-281 (1991), Sato, H.; Dan, T.;Onuma, E.; Tanaka, H.; Aoki, B.; Koga, H.; Chem. Pharm. Bull., 39 (7),1760-1772 (1991)).

Specifically, a base is allowed to react with a solution containingcompound (a-1) to obtain phenoxide, and the phenoxide compound is thenallowed to react with compound (a-2), so as to obtain compound (a-3).

This reaction can be carried out by allowing an appropriate base toreact with the above compound at a ratio between 1 equivalent and anexcessive amount to the compound, in an organic solvent such as acetone,2-butanone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide,benzene or toluene, or a mixed solvent thereof. Examples of a base usedherein may include sodium carbonate, potassium carbonate, sodiumhydroxide, potassium hydroxide, diazabicycloundecen, sodium hydride,potassium hydride, sodium methoxide, potassium methoxide, and potassiumtert-butoxide. Compound (a-2) is used at a ratio between 1 and 3equivalents, and preferably between 1 and 1.7 equivalents, with respectto compound (a-1).

The reaction time is not particularly limited. It is generally between 1and 48 hours, and preferably between 1 and 24 hours.

The reaction temperature is generally between a temperature on ice and asolvent-reflux temperature.

There may be cases where preferred results such as the improvement ofyield or the reduction of the reaction time can be obtained by thecoexistence of an ammonium salt such as tetra-n-butylammonium chloride,tetra-n-butylammonium bromide, or tetra-n-butylammonium iodide.

[Step A-2]

This is a step of obtaining compound (a-4) by subjecting compound (a-3)to a Claisen rearrangement reaction.

This reaction can be carried out under the same conditions as thosedescribed in, for example, Nichols, D. E.; Snyder, S. E.; Oberlender,R.; Johnson, M. P.; Huang, X.; J. Med. Chem., 34 (1), 276-281 (1991),Sato, H.; Dan, T.; Onuma, E.; Tanaka, H.; Aoki, B.; Koga, H.; Chem.Pharm. Bull., 39 (7), 1760-1772 (1991).

Specifically, for example, a solution containing compound (a-3) isheated, so as to obtain compound (a-4).

This reaction can be carried out in the absence of solvent, or in asolvent such as N,N-dimethylaniline, N,N-diethylaniline,N-methylpyrrolidone, or dichlorobenzene.

The reaction temperature is generally between 100° C. and asolvent-reflux temperature, and more preferably between 160° C. and 210°C.

This reaction is preferably carried out in a nitrogen or argonatmosphere. There may be cases where preferred results such as thereduction of the reaction time or the improvement of yield can beobtained by performing this reaction using a microwave reactor.

In addition, there may be cases where a positional isomer is synthesizedin this reaction (Claisen rearrangement), although it depends on thetype of a raw material. When an allyloxy group is defined at position 1,compounds formed by transferring an allyl group to position 2, 4, or 6,are also included in the scope of present invention.

[Step A-3]

This is a step of obtaining compound (a-6) by the methylation reactionof compound (a-4) with compound (a-5).

This reaction can be carried out under the same conditions as those usedin the alkylation (methylation) reaction of a phenol derivative(including a neterocyclic ring) with a methyl halide or dimethyl sulfate(which are conditions described in, for example, Chilin, A.; Rodighiero,P.; Pastorini, G.; Guitto, A.; J. Org. Chem., 56 (3), 980-983 (1991),.Dike, S. Y.; Merchant, J. R.; Sapre, N. Y.; Tetrahedron, 47 (26),4775-4786 (1991)).

Specifically, a base is allowed to react with a solution containingcompound (a-4) to obtain phenoxide, and the phenoxide compound is thenallowed to react with compound (a-5), so as to obtain compound (a-6).

This reaction can be carried out by allowing an appropriate base toreact with the above compound at a ratio between 1 equivalent and anexcessive amount to the compound, in an organic solvent such as acetone,2-butanone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide,benzene or toluene, or a mixed solvent thereof. Examples of a base usedherein may include sodium carbonate, potassium carbonate, sodiumhydroxide, potassium hydroxide, diazabicycloundecen, sodium hydride,potassium hydride, sodium methoxide, potassium methoxide, and potassiumtert-butoxide.

Examples of a methylating reagent may include methyl iodide, methylbromide, methyl chloride, and dimethyl sulfate.

Compound (a-5) is used at a ratio between 1 and 5 equivalents, andpreferably between 1 and 3 equivalents, with respect to compound (a-4).The reaction time is not particularly limited. It is generally between0.5 and 48 hours, and preferably between 0.5 and 24 hours.

The reaction temperature is generally between a temperature on ice and asolvent-reflux temperature.

There may be cases where preferred results such as the improvement ofyield or the reduction of the reaction time can be obtained by thecoexistence of an ammonium salt such as tetra-n-butylammonium chloride,tetra-n-butylammonium bromide, or tetra-n-butylammonium iodide.

In addition, compound (a-6) can be produced from compound (a-4) by thefollowing alternative method.

Alternative Method

For example, to absolution containing compound (a-4), diazomethane,trimethylsilyldiazomethane, or the like is added at a ratio between 1equivalent and an excessive amount, so as to carry out a reaction,thereby obtaining compound (a-6). Examples of a reaction solvent mayinclude ether and methanol. The reaction temperature is generallybetween a temperature on ice and a room temperature. This method hasbeen known to persons skilled in the art. The reaction can be carriedout under the same conditions as those described in, for example, White,J. D.; Butlin, R. J.; Hahn, H. -G.; Johnson, A. T.; J. Am. Chem. Soc.,112 (23), 8595-8596 (1990).

[Step A-4]

This is a step of obtaining compound (1-9) by the oxidative cleavage ofolefin in the allyl part of compound (a-6).

The reaction can be carried out under the same conditions as thosegenerally used in an oxidative cleavage reaction of obtaining aldehydefrom olefin. An oxidative cleavage reaction used in the present reactionis not particularly limited. An oxidative cleavage reaction involvingozone oxidation, the use of osmium tetroxide (wherein an oxidizing agentmay be used in combination), the use of K₂OsO₄ (wherein an oxidizingagent is used in combination), the use of chromic acid, or electrodeoxidation, may be an example of such an oxidative cleavage reaction.

An oxidizing agent is used at a ratio between a catalytic amount (0.01equivalent) and an excessive amount with respect to compound (a-6). Anoxidizing agent that is used in combination is used at a ratio between 1equivalent and an excessive amount with respect to the above oxidizingagent.

Examples of an oxidative cleavage reaction involving ozone oxidation mayinclude methods described in, for example, Jagadeesh, S. G.; Krupadanam,G. L. D.; Srimannarayana, G.; Synth. Commun., 31 (10), 1547-1557 (2001),Cannon, J. G.; Roufos, I.; J. Heterocycl. Chem., 27 (7), 2093-2095(1990).

In an oxidative cleavage reaction involving the ozone oxidation ofolefin, specifically, for example, oxygen current containing severalpercentage of ozone (prepared with an ozone generator) is applied to asolution containing compound (a-6), and then, the generated ozonide(hydroperoxide, when methanol is used as a solvent) is treated with areducing agent without being isolated, so as to obtain compound (1-9).

A solvent used in the present reaction is not particularly limited, aslong as it does not inhibit the reaction and dissolves a startingsubstance to a certain extent. Preferred examples may include methylenechloride, ethyl acetate, and methanol. The reaction temperature isgenerally between −100° C. and a room temperature, and more preferablybetween −78° C. and a room temperature. The reaction time is notparticularly limited. It is generally between 0.5 and 48 hours, andpreferably between 0.5 and 24 hours.

In the treatment with a reducing agent, a reducing agent used under thereaction conditions that are commonly used in the aforementionedoxidative cleavage reaction can be used. Specific examples of such areducing agent may include zinc-acetic acid, triphenylphosphine,triethyl phosphite, catalytic hydrogenation, and dimethyl sulfide.

In addition, the method described in Lai, G.; Anderson, W. K.;Tetrahedron Lett., 34 (43), 6849-6852 (1993) is an example of anoxidative cleavage reaction using osmium tetroxide (wherein an oxidizingagent may be used in combination), K₂OsO₄ (wherein an oxidizing agent isused in combination), AD-mix-α(β), or the like.

The oxidative cleavage reaction of olefin using osmium tetroxide or thelike can be carried out under the same conditions as commonly usedreaction conditions (for example, conditions described in theaforementioned publications).

An oxidizing agent used in combination is not particularly limited. Anexample of such an oxidizing agent may be sodium periodate.

A solvent used herein may be a mixed solvent consisting of water and anorganic solvent such as ether, tetrahydrofuran, 1,4-dioxane, or acetone.The reaction temperature is generally between a temperature on ice and aroom temperature.

An oxidative cleavage reaction using osmium tetroxide can also becarried out by two-step reaction, wherein olefin is oxidized with osmiumtetroxide (that may be used together with an oxidizing agent) into1,2-diol, and then aldehyde is obtained from the 1,2-diol using anoxidizing agent such as lead tetraacetate or sodium periodate.

Such two-step reaction can be carried out under the same conditions ascommonly used reaction conditions (for example, conditions described inMasquelin, T.; Hengartner, U.; Streith, J.; Synthesis, 7, 780-786(1995), Banfield, S. C.; England, D. B.; Kerr, M. A.; Org. lett., 3(21), 3325-3327 (2001)).

Examples of an oxidizing agent used when olefin is converted into1,2-diol may include N-methylmorpholine N-oxide, and K₃Fe(CN)₆. Asolvent used herein is a mixed solvent consisting of water and anorganic solvent such as acetonitrile, acetone, tert-butanol, ortetrahydrofuran. The reaction temperature is generally between atemperature on ice and a room temperature. The reaction time is notparticularly limited. It is generally between 0.2 and 48 hours, andpreferably between 0.2 and 24 hours.

In addition, examples of an oxidizing agent used when 1,2-diol isconverted into aldehyde may include lead tetraacetate and sodiumperiodate. Examples of a solvent used herein may include organicsolvents such as benzene, toluene, methylene chloride, ether,tetrahydrofuran, 1,4-dioxane, or acetone, and mixed solvents consistingof water and these organic solvents. The reaction temperature isgenerally between a temperature on ice and a room temperature. Thereaction time is not particularly limited. It is generally between 5minutes and 48 hours, and preferably between 5-minutes and 24 hours.

[Step A-5]

This is a step of synthesizing compound (a-3) by using compound (a-1) asa raw material and applying the method described in the above productionmethod ([Step A-1]).

[Step A-6]

This is a step of synthesizing compound (a-4) by using compound (a-3) asa raw material and applying the method described in the above productionmethod ([Step A-2]).

[Step A-7]

This is a step of obtaining compound (a-7) by modifying (converting)ring A of compound (a-4) as appropriate. Modification (conversion) ofring A of compound (a-4) of the present invention can be carried out byperforming various reactions known to persons skilled in the art, or bythe combined use of various reactions. The above compound can also beproduced by the method described in production examples in the presentexamples. The term “modification (conversion) of ring A” includes themodification (conversion) of a substituent (R₍₄₎, R₍₅₎, or R₍₆₎).

Specific examples of various reactions known to persons skilled in theart may include: an oxidation of converting alcohol into a carbonylcompound such as aldehyde or ketone; an oxidation of converting analdehyde compound into carboxylic acid; a reduction of converting ester,carboxylic acid, or nitrile into aldehyde or alcohol; a nitrationreaction of an aromatic ring; a halogenation of an aromatic ring; areduction from a nitro group into an amino group; a reduction of acarbon-carbon double bond or a triple bond due to hydrogenation in thepresence of a transition metal catalyst; an esterification of carboxylicacid; hydrolysis of an ester into carboxylic acid; synthesis of analdehyde compound by hydrolysis of an enol ether compound; a conversionof hydrolyzing nitrile into an amide compound or carboxylic acid; areduction of an amide compound into an amino compound; a hydroboration;an oximation of a carbonyl compound such as aldehyde or ketone; anitrilation of an oxime group; an N-alkylation using a reductiveamination; a method of synthesizing amides using an acylation of anamino group; a sulfonamidation of an amino group; an amidation by thecondensation of a carboxylic acid compound and an amino compound; anamidation reaction by the condensation of an ester compound and an aminocompound; an amidation by the condensation of acid chloride and an aminocompound; a condensation between an amino group and a hydroxyl group,which uses N,N′-carbonyldiimidazole, phosgene, or triphosgene; acondensation between amide and a hydroxyl group, which usesN,N′-carbonyldiimidazole, phosgene, or triphosgene; a reaction ofconverting a hydroxyl group into fluorine using a DAST(dimethylaminosulfur trifluoride) reagent or the like; an O-alkylationof alcohol or phenols; an N-alkylation of an amide group; anN-alkylation of an urethane compound; an alkylation of a carbonyl groupinto α-position by a reaction with alkyl halide following the treatmentof a carbonyl compound with a base such as LDA (lithium diisopropylamide); a demethylation reaction from an anisole derivative into aphenol derivative; a reaction of converting a hydroxyl group into aleaving group, such as mesylation or bromination of a hydroxyl group; anucleophilic substitution reaction between a compound having a leavinggroup such as a bromo group and an amine compound; a nucleophilicsubstitution reaction between a compound having a leaving group such asa bromo group and sodium cyanide; a nucleophilic reaction of a carbonylgroup with a Grignard reagent or alkyl or phenyl lithium; Wittigreaction; Horner-Emmons reaction; Mitsunobu reaction; Beckmannrearrangement; synthesis of benzoxazole by Beckmann rearrangement;Curtius rearrangement; Baeyer-Villiger reaction; Dieckmann condensation;a coupling reaction using a transition metal (for example, Suzukicoupling reaction, Ulmann-type coupling reaction, Sonogashira reaction),the coupling reaction of S. L. Buchwald et al. between an amino compoundand halogenated aryl compounds, Stille coupling reaction, etc.); areaction of synthesizing isoxazole by a 1,3-dipole addition; a reactionof synthesizing oxazole using an aldehyde compound and a TOSMIC reagent(tosylmethyl isocyanide); metallation due to halogen-metal exchange; aformylation or amidation due to the reaction between a metallated(lithiated) compound (lithiation, etc.) and a formylating agent such asN,N-dimethylformamide or an amidating agent such as dimethylcarbamoylchloride; a reaction of converting a pyridine compound into a quaternarycompound using methyl iodide or benzyl bromide; a reduction reaction ofa quaternary pyridine compound into piperidine due to hydrogenation inthe presence of a transition metal catalyst; a method of synthesizing aketone compound due to the decarboxylation of a 1,3-ketoester compound;and protection and deprotection of various functional groups describedin the publication, T. W. Green and P. G. M. Wuts, “Protective groups inOrganic Chemistry, Second Edition”, John Wiley & Sons (1991). However,examples are not limited to these reactions.

[Step A-8]

This is a step of synthesizing compound (1-9) by using compound (a-7) asa raw material and applying the above production method ([Step A-4]).

[Step A-9]

This is a step of synthesizing compound (a-9) by using compound (a-1)and compound (a-8) as raw materials and applying the above productionmethod ([Step A-1]) based on the methods described in the publicationssuch as Molina, P., Alajarin, M.; Vidal, A.; Fenau-Dupomt, J.; Declerq,J. P.; J. Org. Chem., 56 (12), 4008-4016 (1991), Mann, A.; Muller, C.;Tyrrell, E.; J. Chem. Soc., Perkin Trans. I, (8), 1427-1438 (1998).

[Step A-10]

This is a step of synthesizing compound (a-10) by using compound (a-9)as a raw material and applying the above production method ([Step A-2]).

This production method may provide preferred results, when the Claisenrearrangement of a 3-methyl-2-butenyl group is conducted in apara-position selective manner to 3-methyl-2-butenyloxy group.

[Step A-11]

This is a step of synthesizing compound (a-11) by appropriatelymodifying ring A, using compound (a-10) as a raw material and applyingthe above production method ([Step A-7]).

[Step-A-12]

This is a step of synthesizing compound (1-9) by-using compound (a-11)as a raw material and applying the above production method ([Step A-4]).

[Step A-13]

This is a step of synthesizing compound (a-3) by using compound (a-1) asa raw material and applying the above production method ([Step A-1]).

[Step A-14]

This is a step of synthesizing compound (a-12) by appropriatelymodifying ring A, using compound (a-3) as a raw material and applyingthe above production method ([Step A-7]).

[Step A-15]

This is a step of synthesizing compound (a-13) by using compound (a-12)as a raw material and applying the above production method ([Step A-2]).

[Step A-16]

This is a step of synthesizing compound (a-14) by appropriatelymodifying ring A, using compound (a-13) as a raw material and applyingthe above production method ([Step A-7]).

[Step A-17]

This is a step of synthesizing compound (1-9) by using compound (a-14)as a raw material and applying the above production method ([Step A-4]).

[Step A-18]

This is a step of synthesizing compound (a-15) by using compound (a-13)as a raw material and applying the above production method ([Step A-3]).

[Step A-19]

This is a step of synthesizing compound (1-9) by using compound (a-15)as a raw material and applying the above production method ([Step A-4]).[General Production Method-B] (Synthesis Method of Compound (1-9))

wherein each of ring A, R₍₄₎, R₍₅₎, R₍₆₎, R′₍₄₎, R′₍₅₎, R′₍₆₎, R″₍₄₎,R″₍₅₎, and R″₍₆₎ has the same meaning as described above; P₍₂₎represents a protecting group for a hydroxyl group, which is —CH(Me)₂ orthe like formed by a methyl group, an ethyl group, or P₍₂₎ attaching toa carbon atom adjacent thereto; L(₂) represents a leaving group, whichis a halogen atom (chlorine atom, bromine atom, iodine atom), or asulfonyloxy group such as a methanesulfonyloxy group,p-toluenesulfonyloxy group, or trifluoromethanesulfonyloxy group.

A commercially available product may directly be used as compound (a-1),or the above compound may also be produced from a commercially availableproduct by a method known to persons skilled in the art. Moreover, itcan also be produced by production examples in the present examples.

A commercially available product may directly be used as compound (b-2),or the above compound may also be produced from a commercially availableproduct by a method known to persons skilled in the art.

[Step B-1]

This is a step of synthesizing compound (b-3) by using compound (a-i) asa raw material and applying the above production method ([Step A-1]).

[Step B-2]

This is a step of synthesizing compound (b-4) by using compound (b-3) asa raw material and applying the above production method ([Step A-2]).

[Step B-3]

This is a step of synthesizing compound (b-5) by using compound (b-4) asa raw material and applying the above production method ([Step A-3]).

[Step B-3-1-1]

This is a step of synthesizing compound (b-6) by appropriately modifyingring A, using compound (b-5) as a raw material and applying the aboveproduction method ([Step A-7]).

[Step B-3-1-2]

This is a step of synthesizing compound (b-7) by using compound (b-6) asa raw material and applying the above-production method ([Step A-4]).

[Step B-3-1-3]

This is a step of obtaining compound (b-8) by protecting 1,2-diol ofcompound (b-7).

The reaction can be carried out under the same conditions as thosecommonly used for the protection of 1,2-diol (for example, conditionsdescribed in publications such as T. W. Green and P. G. M. Wuts,“Protective groups in Organic Chemistry, Second Edition”, John Wiley &Sons (1991), pp. 118-142).

For example, a protecting group (acetonide) can be introduced into1,2-diol under conditions in which 2,2-dimethoxypropane, pyridiump-toluenesulfonate at a catalytic amount, and the like, are allowed toreact with the above compound in an acetone solvent.

[Step B-3-1-4]

This is a step of obtaining compound (1-9) by using compound (b-8) as araw material and applying the above production method ([Step A-7]). Bythis method, ring A is modified (converted) as appropriate, theprotecting group of 1,2-diol is deprotected, and oxidative cleavage isconducted, thereby obtaining the compound of interest.

The reaction can be carried out under the same conditions as thosecommonly used in the deprotection of 1,2-diol (for example, conditionsdescribed in publications such as T. W. Green and P. G. M. Wuts,“Protective groups in Organic Chemistry, Second Edition”, John Wiley &Sons (1991), pp. 118-142.).

For example, 1,2-diol can be obtained by deprotecting the protectinggroup (acetonide) of 1,2-diol under conditions in which a 4N hydrogenchloride-ethyl acetate solution is allowed to act on the compound in anethyl acetate solvent.

Oxidative cleavage can be carried out using the method described in theabove production method ([Step A-4]).

[Step B-3-2-1]

This is a step of synthesizing compound (1-9) by using compound (b-6) asa raw material and applying the above production method ([Step A-4]).

[Step B-3-3-1]

This is a step of synthesizing compound (1-9) by using compound (b-5) asa raw material and applying the above production method ([Step A-4]).

[Step B-3-4-1]

This is a step of synthesizing compound (b-9) by using compound (b-5) asa raw material and applying the above production method ([Step A-4]).

[Step B-3-4-2].

This is a step of synthesizing compound (b-10) by using compound (b-9)as a raw material and applying the above production method ([StepB-3-1-3]).

[Step B-3-4-3]

This is a step of synthesizing compound (b-11) by appropriatelymodifying ring A, using compound (b-10) as a raw material and applyingthe above production method ([Step A-7]).

[Step B-3-4-4]

This is a step of synthesizing compound (b-12) by using compound (b-11)as a raw material and applying the above production method ([StepB-3-1-4]).

[Step B-3-4-5]

This is a step of synthesizing compound (1-9) by using compound (b-12)as a raw material and applying the above production method ([Step A-4]).[General Production Method C] (Synthesis Method of Compound (1-9))

wherein each of ring A, R₍₄₎, R₍₅₎, R₍₅₎, R′₍₄₎, R′₍₅₎, and R′₍₆₎ hasthe same meaning as described above.

A commercially available product may directly be used as compound (c-1),or the above compound may also be produced from a commercially availableproduct by a method known to persons skilled in the art. Moreover, itcan also be produced using production examples in the present examples,or the method described in [General production method C′] or the like.

[Step C-1]

This is a step of obtaining compound (c-2), which has one more carbonatom by Wittig reaction.

The reaction can be carried out under same conditions as those commonlyused for aldehyde and a Wittig reagent (Wittig reaction)(methoxymethyltriphenylphosphonium chloride) (for example, conditionsdescribed in Gibson, S. E.; Guillo, N.; Middleton, R. J,; Thuilliez, A.;Tozer, M. J.; J. Chem. Soc., Perkin Trans. I, 4, 447-455 (1997)).

Specifically, for example, a Wittig reagent(methoxymethyltriphenylphosphonium chloride) is allowed to react with abase, and it is then allowed to react with compound (c-1), so as toobtain compound (c-2).

The present reaction can be carried out by allowing a base to act on aWittig reagent at a ratio between 0.8 and 1 equivalent with respect tothe reagent in an organic solvent such as ether, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, benzene, or toluene. Examples of abase used herein may include sodium hydride, potassium hydride, sodiummethoxide, potassium methoxide, potassium tert-butoxide, n-butyllithium,and LDA (lithium diisopropylamide).

The reaction time is not particularly limited. It is generally between 5minutes and 24 hours, and preferably between 5 minutes and 12 hours.

The reaction temperature is generally between −78° C. and a roomtemperature, and more preferably between a temperature on ice and a roomtemperature.

[Step C-2]

This is a step of obtaining compound (1-9) by allowing compound (c-2) toreact with acid.

The reaction can be carried out under the same conditions as thosedescribed in, for example, Gibson, S. E.; Guillo, N.; Middleton, R. J.;Thuilliez, A.; Tozer, M. J.; J. Chem. Soc., Perkin Trans. I, 4, 447-455(1997).

Specifically, for example, compound (c-2) is dissolved in 5Nhydrochloric acid or the like followed by heating, so as to obtaincompound (1-9).

The reaction can be carried out by allowing acid to react with the abovecompound at a ratio between 1 equivalent and an excessive amount to thecompound, in a mixed solvent consisting of water and an organic solventsuch as methanol, ethanol, tetrahydrofuran, or 1,4-dioxane, or in anorganic solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane,ethyl acetate, methylene chloride, or acetonitrile. Preferred examplesof acid used herein may include hydrogen chloride, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, trifluoroacetic acid, andformic acid. In addition, it is also possible to convert the compoundinto aldehyde with trimethylsilyl iodide (which may be generated fromtrimethylsilyl chloride and sodium iodide in the reaction system).

The reaction time is not particularly limited. It is generally between0.5 and 24 hours, and preferably between 0.5 and 12 hours.

The reaction temperature is generally between a temperature on ice and asolvent-reflux temperature.

[Step C-3]

This is a step of synthesizing compound (c-3) by appropriately modifyingring A, using compound (c-2) as a raw material and applying the aboveproduction method ([Step A-7]).

[Step C-4]

This is a step of synthesizing compound (1-9) by using compound (c-3) asa raw material and applying the above production method ([Step C-2]).

Compound (c-1) can also be produced by [General production method C′] or[General production method C″], for example.[General Production Method C′] (Synthesis Method of Compound (c-1))

wherein each of ring A, R₍₁₎, R₍₄₎, R₍₅₎, and R(₆) has the same meaningas described above; X represents a halogen atom such as a chlorine atomor bromine atom, a trifluoromethanesulfonyloxy group, or the like; and Mrepresents a metal atom such as lithium or magnesium.

A commercially available product may directly be used as compound(c′-1), compound (c′-2), or compound (c′-3). These compounds may also beproduced from commercially available products by methods known topersons skilled in the art. Moreover, they can also be produced byproduction examples in the present examples.

[Step C′ 1-1]

This is a step of producing a cyano compound (c′-4) by allowing compound(c′-1) to react with a metal cyanide compound in the presence or absenceof an organometallic catalyst.

A substitution reaction of a metal cyanide with a halogenated aryl(including a heterocyclic ring) compound is a method known to personsskilled in the art. This reaction is carried out under the sameconditions as those described in, for example, Bouyssou, P.; Legoff, C.;Chenault, J.; J. Heterocycl. Chem.; 29 (4), 895-898 (1992), Agarwal, A.;Jalluri, R. K.; Blanton, C. D. J.; Taylor, E. W.; Synth. Commun., 23(8), 1101-1110 (1993), Tschaen, D. M.; Desmond, R.; King, A. O.; Fortin,M. C.; Pipik, B.; King, S.; Verhoeven, T. R.; Synth. Commun. 24 (6),887-890 (1994), Tschaen, D. M.; Abramson, L.; Cai, D.; Desmond, R.;Dolling, U. -H.; Frey, L.; Karady, S.; Shi, Y, Y. -J.; Verhoeven, T. R.;J. Org. Chem., 60 (14), 4324-4330 (1995).

[Step C′ 1-2]

This is a step of producing compound (c′-5) by allowing compound (c′-1)to react with an organometallic compound in the presence of anorganometallic catalyst.

This reaction can be carried out under the same conditions as thosecommonly used in the coupling reaction of a halogenated aryl (includinga heterocyclic ring) compound or the like with an organometalliccompound in the presence of an organometallic catalyst. For example, areaction using a tin reagent as such an organometallic compound isdescribed in publications such as Martorell, G.; Garcia-Raso, A.; Saa,J. M.; Tetrahedron Lett., 31 (16), 2357-2360 (1990), Kiely, J. S.;Laborde, E.; Lesheski, L. E.; Bucsh, R. A.; J. Heterocycl. Chem., 28 (6)1581-1585 (1991). A reaction using a boron compound as such anorganometallic compound is described in publications such as Kerins, F.;O' Shea, D. F.; J. Org. Chem., 67 (14), 4968-4971 (2002). A reactionusing a magnesium reagent as such an organometallic compound isdescribed in publications, such as Park, M.; Buck, J. R.; Rizzo, C. J.;Tetrahedron, 54 (42), 12707-12714 (1998). A reaction using a zincreagent as such an organometallic compound is described in publicationssuch as Mohanakrishnan, A. K.; Cushman, M.; Synlett, 7, 1097-1099(1999).

An organometallic catalyst used in the present reaction is notparticularly limited. Preferred examples of such an organometalliccatalyst may include tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),bis(tert-butylphosphine)palladium(0),(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride,palladium(II) acetate, and(1,3-bis(diphenylphosphino)propane)nickel(II). Such an organometalliccatalyst is used at a ratio between approximately 0.001 and 0.1equivalent with respect to a raw material.

An organometallic compound is not particularly limited. Preferredexamples of such an organometallic compound may include organotinreagents such as vinyl tri-n-butyl tin, and organoboron compounds suchas 2,4,6-trivinyl cyclotriboroxane. Such an organometallic compound isused at a ratio between 1 and 5 equivalents with respect to a rawmaterial.

A solvent used in the present reaction is not particularly limited, aslong as it does not inhibit the-reaction. Preferred examples of such asolvent may include benzene, toluene, xylene, N,N-dimethylformamide,1-methyl-2-pyrrolidone, tetrahydrofuran, 1,4-dioxane, acetonitrile, andpropionitrile. The reaction temperature is not particularly limited. Itis generally between a temperature on ice and a solvent-refluxtemperature, and preferably between a room temperature and asolvent-reflux temperature. The reaction time is not particularlylimited. It is generally between 1 and 48 hours, and preferably between1 and 24 hours.

There may be cases where good results such as the improvement of yieldcan be obtained by performing the present reaction in the coexistence ofa base. Such a base is not particularly limited. Preferred examples of abase may include sodium carbonate, potassium carbonate, cesiumcarbonate, potassium phosphate, and trimethylethyleneamine.

[Step C′ 1-3]

This is a step of obtaining an aryl metallic compound (c′-6) byperforming the halogen metal exchange of a halogenated aryl compound(including a heterocyclic compound).

Such a halogen metal exchange can be carried out by a method known topersons skilled in the art. Specifically, for example, compound (c′-1)is subjected to a halogen metal exchange using a commercially availableorganometallic reagent, and preferably, an alkyllithium reagent such asn-, sec-, or tert-butyllithium, and a Grignard reagent such asisopropylmagnesium bromide, or metal magnesium, so as to prepare thecorresponding aryl (including a heterocyclic ring) lithium reagent, oraryl (including a heterocyclic ring) magnesium reagent. A solvent usedin the present step differs depending on a starting material or areagent used. Such a solvent is not particularly limited, as long as itdoes not inhibit the reaction, dissolves a starting substance to acertain extent, and is constantly inactive during the reaction.Preferred examples of such a solvent may include diethyl ether,tetrahydrofuran, benzene, and toluene. The reaction time is notparticularly limited. It is generally between 0.1 and 48 hours, andpreferably between 0.1 and 2 hours. The reaction temperature differsdepending on a starting material or a reagent used. In order to reducethe generation of by products to the minimum, it is preferable tomaintain the temperature to be low, such as a temperature of −78° C.

In addition, there may be cases where good results such as theimprovement of yield or the reduction of the reaction time can beobtained by adding TMEDA (tetramethylethylenediamine), HMPA(hexamethylphosphoroamide), or the like, as an additive.

[Step C′ 1-4]

This is a step of obtaining an aryl metallic compound (c′-6) by themetallation reaction of an aryl (including a heterocyclic compound)compound (c′-2).

The metallation reaction of an aryl compound (including a heterocycliccompound) can be carried out by a method known to persons skilled in theart. Specifically, for example, a commercially available organic metalreagent, and preferably, an alkyllithium reagent such as n-, sec-, ortert-butyllithium, is allowed to act on compound (c′-2), so as toprepare the corresponding aryl (including a heterocyclic ring) lithiumreagent (c′-6).

Such a reaction can be carried out under the same conditions as thosedescribed in, for example, Jacob, P. III; Shulgin, A. T.; Synth.Commun., 11 (12), 957 (1981) or the like.

A solvent used in the present step differs depending on a startingmaterial or a reagent used. Such a solvent is not particularly limited,as long as it does not inhibit the reaction, dissolves a startingsubstance to a certain extent, and is constantly inactive during thereaction. Preferred examples of such a solvent may include diethylether, tetrahydrofuran, benzene, and toluene. The reaction temperaturediffers depending on a starting material or a reagent used. In order toreduce the generation of by products to the minimum, it is preferable tomaintain the temperature to be low, such as a temperature of −78° C. Thereaction time is not particularly limited. It is generally between 0.1and 48 hours, and preferably between 0.1 and 24 hours.

In addition, there may be cases where good results such as theimprovement of yield or the reduction of the reaction time can beobtained by adding TMEDA (tetramethylethylenediamine), HMPA(hexamethylphosphoroamide), or the like, as an additive.

[Step C′ 1-5]

This is a step of obtaining an ester or carboxylic acid compound (c′-7)by subjecting halogenated aryl (including a heterocyclic compound) or anaryl triflate compound (including a heterocyclic compound) (C′-1) to acarbon monoxide insertion reaction.

When a carbon monoxide insertion reaction is carried out using atransition metal catalyst, and preferably, a commercially availablepalladium complex such as palladium(I-I) acetate, in the coexistence ofalcohol, such as preferably methanol, ethanol, or tert-butanol, undercommon conditions that have been known to persons skilled in the art, ahalogen atom can be converted into a desired carboxylate group.Subsequently, alkaline hydrolysis or acid hydrolysis is carried outunder common conditions known to persons skilled in the art, so as toobtain the corresponding carboxylic acid compound.

[Step C′ 1-6]

This is a step of synthesizing compound (c′-7) by using compound (c′-3)as a raw material and applying the method described in the aboveproduction method ([Step A-3]).

[Step C′ 2-1]

This is a step of obtaining compound (c-1) by subjecting compound (c′-4)to a reduction reaction.

As a reduction reaction of converting a cyano group into a formyl group,a reduction reaction of using metal hydride such as diisobutyl aluminumhydride in an inactive solvent such as tetrahydrofuran, has been knownto persons skilled in the art. In addition, the above compound can alsobe produced by a reduction reaction of using Raney nickel described inT. Sohda et al. (Chem. Pharm. Bull., 39 (6), 1440-1445 (1991)) or O .G.Backeberg et al. (J. Chem. Soc., 3961-3963 (1962)) (which is means forheating the compound in a formic acid-water mixed solvent, or means forallowing the compound to react with sodium hypophosphite in apyridine-acetic acid-water mixed solvent at a temperature between a roomtemperature and 40° C.). The reaction time is not particularly limited.It is generally between 0.5 and 48 hours, and preferably between 0.5 and24 hours.

[Step C′ 2-2]

This is a step of synthesizing compound (c-1) by using compound (c′-5)as a raw material and applying the above production method ([Step A-4]).

[Step C′ 2-3]

This is a step of obtaining an aldehyde compound (c-1) from the arylmetallic compound (c′-6) prepared in the above described [Step C′ 1-3]or [Step C′ 1-4].

The aryl metallic compound (c′-6) prepared in the above described [StepC′ 1-3] or [Step C′ 1-4] is allowed to react with a commerciallyavailable formylating agent, and preferably, with a reagent such asN,N-dimethylformamide, N-formylmorpholine, or ethyl formate, so as toproduce the corresponding aldehyde compound (c-1). This formylationreaction has been known to persons skilled in the art.

[Step C′ 2-4]

This is a step of obtaining an ester or carboxylic acid compound (c′-7)from the aryl metal compound (c′-6) prepared in the above described[Step C′ 1-3] or [Step C′ 1-4].

The aryl metallic compound (c′-6) prepared in the above described [StepC′ 1-3] or [Step C′ 1-4] is allowed to react with a commerciallyavailable esterifying agent, and preferably, with a reagent such asdiethyl carbonate or carbon dioxide, so as to convert the above compoundinto the corresponding ester or carboxylic acid compound (c′-7). Thisreaction of converting the compound into an ester or carboxylic acid hasbeen known to persons skilled in the art.

[Step C′ 2-5]

This is a step of obtaining compound (c-1) by subjecting compound (c′-7)to a reduction reaction. The reaction can be carried out under the sameconditions as those commonly used in the reduction reaction from anester compound to an aldehyde compound (for example, conditionsdescribed in E. Winterfeldt; Synthesis, 617 (1975)).

Preferred reducing agents used in the reaction include diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, andbis(N-methylpiperazino)aluminum hydride.

A solvent used in the reaction is not particularly limited, as long asit does not inhibit the reaction and dissolves a starting substance to acertain extent. Preferred examples of such a solvent may includetetrahydrofuran, toluene, and methylene chloride.

The reaction time is not particularly limited. It is generally between0.5 and 48 hours, and preferably between 0.5 and 24 hours.

The reaction temperature is not particularly limited. It is generallybetween −78° C. and a room temperature, and preferably between −78° C.and a temperature on ice.

[Step C′ 2-6]

This is a step of obtaining an alcohol compound (c′-8) by subjecting anester compound (c′-7) to a reduction reaction.

The alcohol compound (c′-8) can be obtained from an ester or carboxylicacid compound (c′-7) according toga method known to persons skilled inthe art.

In the case of an ester, examples of a reducing agent used in thereaction may include lithium aluminum hydride, lithium borohydride, anddiisobutyl aluminum hydride. The reaction temperature is notparticularly limited. It is generally between −78° C. and asolvent-reflux temperature, and preferably between −78° C. and a roomtemperature. A solvent used in the reaction is not particularly limited,as long as it does not inhibit the reaction and dissolves a startingsubstance to a certain extent. Preferred examples of such a solvent mayinclude tetrahydrofuran, ether, toluene, and methylene chloride.

In the case of carboxylic acid, examples of a reducing agent used in thereaction may include lithium aluminum hydride, a borane-tetrahydrofurancomplex, and a borane-dimethylsulfide complex. The reaction temperatureis not particularly limited. It is generally between −78° C. and asolvent-reflux temperature, and preferably between a temperature on iceand a solvent-reflux temperature. A solvent used in the reaction is notparticularly limited, as long as it does not inhibit the reaction anddissolves a starting substance to a certain extent. Preferred examplesof such a solvent may include tetrahydrofuran and ether. The reactiontime is not particularly limited. It is generally between 0.5 and 48hours, and preferably between 0.5 and 24 hours.

[Step C′ 2-7]

This is a step of obtaining an aldehyde compound (c-1) by subjecting analcohol compound (c′-8) to an oxidation reaction. An aldehyde compoundcan be obtained from an alcohol compound according to a method known topersons skilled in the art.

Examples of a known oxidation method used in the present reaction mayinclude Swern oxidation, Corey-Kim oxidation, Moffatt oxidation, PCCoxidation, PDC oxidation, Dess-Martin oxidation, SO₃-pyridine oxidation,and manganese dioxide oxidation.

A solvent used in the reaction is not particularly limited, as long asit does not inhibit the reaction and dissolves a starting substance to acertain extent. Preferred examples of such a solvent may includedimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, andchloroform.

The reaction temperature is not particularly limited. It is generallybetween −78° C. and a solvent-reflux temperature, and preferably between−78° C. and a room temperature. The reaction time is not particularlylimited. It is generally between 0.5 and 48 hours, and preferablybetween 0.5′and 24 hours.[General Production Method C″] (Synthesis Method of Compound (c-1))

wherein each of ring A, R₍₄₎, R₍₅₎, and R₍₆₎ has the same meaning asdescribed above; and L₍₁₎ represents a halogen atom such as a chlorineatom or bromine atom.

A commercially available product may directly be used as compound(c″-1), or the above compound may also be produced from a commerciallyavailable product by a method known to persons skilled in the art.Moreover, it can also be produced by production examples in the presentexamples.

[Step C″ 1-1]

This is a step of obtaining compound (c″-2) via the successivetreatment, in which the halogen metal exchange of compound (c″-1) isperformed and the resultant metal compound is treated with trialkylborate such as trimethyl borate to give a boronic acid derivative, whichis treated with an oxidizing reagent such as peracetic acid orN-methylmorpholine N-oxide to produce compound (c″-2).

Such a reaction via boronic acid is a synthesis method that has beenknown to persons skilled in the art. The reaction can be carried outunder the same conditions as those described in, for example, Gotteland,J. -P.; Halazy, S.; Synlett, 9, 931-932 (1995).

[Step C″ 1-2]

This is a step of synthesizing compound (c″-3) by using compound (c″-2)as a raw material and applying the above production method ([Step A-3]).

[Step C″ 1-3]

This is a step of obtaining compound (c″-⁴) by the halogenation reactionof compound (c″-3).

This halogenation reaction is a synthesis method that has been known topersons skilled in the art. The reaction can be carried out under thesame conditions as those described in, for example, Gray, M. A.;Konopski, L.; Langlois, Y.; Synth. Commun., 24 (10), 1367-1379 (1994).

[Step C″ 1-4]

This is a step of obtaining compound (c-1) from compound (c″-4).

The method of producing compound (c-1) is a synthesis method that hasbeen known to persons skilled in the art. The reaction can be carriedout under the same conditions as those described in, for example,Valenti, P.; Chiarini, A.;.Gasperi, F.; Budriesi, R.; Arzneim.-Forsch.,40 (2), 122-125 (1990); Ventelon, L.; Moreaux, L.; Mertz, J.;Blanchard-Desce, M.; Chem. Commun. (Cambridge), 20, 2055-2056 (1999).[General Production Method D] (Synthesis Method of Compound (1-9))

wherein each of ring A, R₍₄₎, R₍₅₎, R₍₆₎, R′₍₄₎, R′₍₅₎, R′₍₆₎, X, and Mhas the same meaning as described above; R₍₇₎ represents a hydrogen atomor a lower alkyl group such as a methyl group or ethyl group; and R₍₈₎represents a lower alkyl group such as a methyl group or ethyl group.

Commercially available products may directly be used as compound (d-1),compound (d-2), and compound (d-5). Otherwise, these compounds may alsobe produced from commercially available products by methods known topersons skilled in the art. Moreover, these compounds may also beproduced by production examples in the present examples.

[Step D-1]

This is a step of producing compound (d-3) by allowing compound (d-1) toreact with an organometallic compound (d-2) in the presence of anorganometallic catalyst.

This reaction can be carried out under the same conditions as thosecommonly used in the coupling reaction of a halogenated heteroarylcompound or the like with an organometallic compound in the presence ofan organometallic catalyst.

For example, a reaction of using an organic tin reagent as an organicmetal compound is described in publications such as Mckittrick, B.;Failli, A.; Steffan, R. J.; Soll, R. M.; Hughes, P.; Schmid, J.;Asselin, A. A.; Shaw, C. C.; Noureldin, R.; Gavin, G.; J. Heterocycl.Chem., 27 (7), 2151-2163 (1990). A reaction of using an organic zincreagent as an organometallic compound is described in publications suchas Campbell James B. (JR), Firor Judy Wawerchak, Davenport Timothy W.,Synth. Commun., 19, 2265-2272 (1989).

An organometallic catalyst used in the present reaction is notparticularly limited. Preferred examples of such an organic metalcatalyst may include tetrakis(triphenylphosphine) palladium(0),dichlorobis(triphenylphosphine) palladium(II),(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride,bis(tert-butylphosphine)palladium(0), palladium(II) acetate, and(1,3-bis(diphenylphosphino)-propane)nickel(II). Such an organometalliccatalyst is used at a ratio between approximately 0.001 and 0.1equivalent with respect to a raw material.

An organometallic compound is not particularly limited. Preferredexamples of such an organometallic compound may include organic tinreagents such as aryl tri-n-butyl tin ortributyl(3-methyl-2-butenyl)tin, and organic boron reagents such as arylboronic acid or 2-aryl-4,4,5,5-tetramethyl-1,3-dioxaborolane. Such anorganic metal compound is used at a ratio between 1 and 5 equivalentswith respect to a raw material.

A solvent used in the present reaction is not particularly limited, aslong as it does not inhibit the reaction. Preferred examples of such asolvent may include benzene, toluene, xylene, N,N-dimethylformamide,1-methyl-2-pyrrolidone, tetrahydrofuran, 1,4-dioxane, acetonitrile, andpropionitrile. The reaction temperature is not particularly limited. Itis generally between a temperature on ice and a solvent-refluxtemperature, and preferably between a room temperature and asolvent-reflux temperature. The reaction time is not particularlylimited. It is generally between 0.5 and 48 hours, and preferablybetween 0.5 and 24 hours.

There may be cases where good results such as the improvement of yieldcan be obtained by performing the present reaction in the coexistence ofa base. Such a base is not particularly limited. Preferred examples of abase may include sodium carbonate, potassium carbonate, cesiumcarbonate, potassium phosphate, and triethylamine.

[Step D-2]

This is a step of synthesizing compound (d-4) by appropriately modifyingring A, using compound (d-3) as a raw material and applying the aboveproduction method ([Step A-7]).

[Step D-3]

This is a step of synthesizing compound (1-9) by using compound (d-4) asa raw material and applying the above production method ([Step A-4]).

[Step D-4]

This is a step of producing compound (d-6) by allowing compound (d-1) toreact with compound (d-5) in the presence of an organometallic catalyst.

This reaction can be carried out under the same conditions as thosecommonly used in the coupling reaction of a halogenated heteroarylcompound or the like with a vinyl ether compound or the like in thepresence of an organometallic catalyst.

For example, the reaction can be carried out under the same conditionsas those described in, for example, Andersson, C, -M.; Larsson, J.;Hallberg, A.; J. Org. Chem., 55 (22), 5257-5761 (1990).

An organometallic catalyst used in the present reaction is notparticularly limited. Preferred examples of such an organic metalcatalyst may include tetrakis(triphenylphosphine) palladium(0),dichlorobis(triphenylphosphine) palladium(II),(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride,palladium(II) acetate, and(1,3-bis(diphenylphosphino)propane)nickel(II). Such an organic metalcatalyst is used at a-ratio between approximately 0.001 and 0.1equivalent with respect to a raw material.

A solvent used in the present reaction is not particularly limited, aslong as it does not inhibit the reaction. Preferred examples of such asolvent may include benzene, toluene, xylene, N,N-dimethylformamide,.1-methyl-2-pyrrolidone, tetrahydrofuran, 1,4-dioxane, acetonitrile, andpropionitrile. The reaction temperature is not particularly limited. Itis generally between a temperature on ice and a solvent-refluxtemperature, and preferably between a room temperature and asolvent-reflux temperature. The reaction time is not particularlylimited. It is generally between 0.5 and 48 hours, and preferablybetween 0.5 and 24 hours.

There may be cases where good results such as the improvement of yieldcan be obtained by performing the present reaction in the coexistence ofa base. Such a base is not particularly limited. Preferred examples of abase may include sodium carbonate, potassium carbonate, cesiumcarbonate, potassium phosphate, and triethylamine.

There may also be cases where preferred results such as the improvementof yield or the reduction of the reaction time can be obtained by thecoexistence of an ammonium salt such as tetra-n-butylammonium chloride,tetra-n-butylammonium bromide, or tetra-n-butylammonium iodide.

[Step D-5]

This is a step of synthesizing compound (d-7) by appropriately modifyingring A, using compound (d-6) as a raw material and applying the aboveproduction method ([Step A-7]).

[Step D-6]

This is a step of synthesizing compound (1-9) by using compound (d-7) asa raw material and applying the above production method ([Step C-2]).

[Step D-7]

This is a step of synthesizing compound (1-9) by using compound (d-6) asa raw material and applying the above production method ([Step C-2]).[General Production Method E] (Synthesis Method of Compound (1-9) andCompound (1-10))

wherein each of ring A, R₍₄₎, R₍₅₎, R₍₅₎, X, and M represents the samemeaning as described above; X′ represents a leaving group that is, forexample, a halogen atom (a chlorine atom, bromine atom, iodine atom,etc.) or a sulfonyloxy group such as a methanesulfonyloxy group,p-toluenesulfonyloxy group, or trifluoromethanesulfonyloxy group.

Commercially available products may directly be used As compound (c′-l)and compound (c′-2). The above compounds may also be produced fromcommercially available products by methods known to persons skilled inthe art. Moreover, these compounds can also be produced by productionexamples in the present examples.

[Step E1-1]

This is a step of synthesizing compound (c′-5) by using compound (c′-1)as a raw material and applying the above production method ([StepC′1-2]).

[Step E1-2]

This is a step of synthesizing compound (c′-6) by using compound (c′-1)as a raw material and applying the above production method ([StepC′1-3]).

[Step E1-3]

This is a step of synthesizing compound (c′-6) by using compound (c′-2)as a raw material and applying the above production method ([StepC′1-4]).

[Step E2-1]

This is a step of obtaining compound (e-3) by hydroboration of compound(c′-5).

Hydroboration of olefin is carried out by a common method that has beenknown to persons skilled in the art, so as to obtain an alcoholcompound.

[Step E2-2]

This is a step of obtaining compound (e-3) by allowing a metallated arylcompound (including a heterocyclic ring) (C′-6) to react with ethyleneoxide.

A metallated aryl compound (including a heterocyclic ring) is allowed toreact with ethylene oxide according to a general method known to personsskilled in the art, so as to obtain an alcohol compound.

[Step E3-1]

This is a step of obtaining compound (1-10) by converting a hydroxylgroup of compound (e-3) into a leaving group.

Examples of a leaving group may include halogen atoms (a chlorine atom,bromine atom, iodine atom, etc.) and sulfonyloxy groups such as amethanesulfonyloxy group, p-toluenesulfonyloxy group, ortrifluoromethanesulfonyloxy group.

This reaction can be carried out under the same conditions as thosecommonly used in a reaction of converting a hydroxyl group into theabove leaving groups (conditions described in, for example, R. K.Crossland and K. L. Servis, J. Org. Chem., 35, 3195 (1970)).

When such a leaving group is a halogen atom for example, compound (1-10)can be produced by allowing compound (e-3) to react with thionylchloride, thionyl bromide, phosphorus tribromide,tetrahalogenomethane-triphenylphosphine, or the like. A solvent used inthe reaction is not particularly limited, as long as it does not inhibitthe reaction and dissolves a starting substance to a certain extent.Preferred examples of such a solvent may include benzene, toluene,xylene, methylene chloride, and chloroform.

The reaction temperature is generally between −78° C. and asolvent-reflux temperature, and preferably between a temperature on iceand a solvent-reflux temperature.

The reaction time is not particularly limited. It is generally between 5minutes and 48 hours, and preferably between 5 minutes and 12 hours.

When such a leaving group is a sulfonyloxy group for example, compound(1-10) can be produced by allowing compound (e-3) to react withmethanesulfonyl chloride, p-toluenesulfonyl chloride,trifluoromethanesulfonic anhydride, or the like.

A solvent used in the reaction is not particularly limited, as long asit does not inhibit the reaction and dissolves a starting substance to acertain extent. Preferred examples of such a solvent may includetetrahydrofuran, toluene, xylene, methylene chloride, chloroform, andN,N-dimethylformamide.

The reaction temperature is generally between −78° C. and asolvent-reflux temperature, and preferably between −78° C. and a roomtemperature. There may be cases where good results such as theimprovement of yield can be obtained by addition of a base. A base usedherein is not particularly limited, as long as it does not inhibit thereaction. Preferred examples of such a base may include sodiumcarbonate, potassium carbonate, triethylamine, pyridine, anddiisopropylethylamine.

[Step E3-2]

This is a step of obtaining compound (1-9) by subjecting compound (e-3)to an oxidation reaction. An aldehyde compound can be obtained from analcohol compound according to a method known to persons skilled in theart.

Examples of a known oxidation method used in the present reaction mayinclude Swern oxidation, Corey-Kim oxidation, Moffatt oxidation, PCCoxidation, PDC oxidation, Dess-Martin oxidation, SO₃-pyridine oxidation,and TEMPO oxidation.

A solvent used in the reaction is not particularly limited, as long asit does not inhibit the reaction and dissolves a starting substance to acertain extent. Examples of such a solvent may include dimethylsulfoxide, tetrahydrofuran, toluene, methylene chloride, and chloroform.

The reaction temperature is not particularly limited. It is generallybetween −78° C. and a solvent-reflux temperature, and preferably between−78° C. and a room temperature. The reaction time is not particularlylimited. It is generally between 5 minutes and 48 hours, and preferablybetween 5 minutes and 24 hours.

[General Production Method F] (Synthesis Method of Compound (2-1))

[General production method F] is a method for producing compound (2-1)that is used in [General production method 2′].

wherein R₍₉₎ has the same meaning as described above; and R₍₁₄₎represents a lower alkyl group such as a methyl group or ethyl group, oran aralkyl group such as a benzyl group.[Step F-1]

This is a step of obtaining compound (2-1) by allowing compound (f-1) toreact with a primary amine (f-10).

This reaction has been known to persons skilled in the art. It can becarried out under the same conditions as those described in, forexample, Tschaen, D. M.; Abramson, L.; Cai, D.; Desmond, R.; Dolling, U.-H.; Frey, L.; Karady, S. Shi, Y. -J.; Verhoeven, T. R.; J. Org. Chem.,60 (14), 4324-4330 (1995).

[Step F-2]

This is a step of synthesizing compound (f-4) by using compound (f-3) asa raw material and applying the above production method ([Step 1-6]) or([Step 1-7]).

[Step F-3]

This is a step of obtaining compound (2-1) by hydrolysis of compound(f-4). This reaction can be carried out under the same conditions asthose commonly used in the hydrolysis of a ketal compound (for example,conditions described in publications such as T. W. Green and P. G. M.Wuts, “Protective groups in Organic Chemistry, Second Edition”, JohnWiley & Sons (1991), pp. 175-223).

The reaction is carried out in the presence of acid. Examples of acidused herein may include hydrochloric acid, p-toluenesulfonic acid,trifluorosulfonic acid, and camphorsulfonic acid. A solvent used in thereaction is not particularly limited, as long as it does not inhibit thereaction and dissolves a starting substance to a certain extent.Preferred examples of a solvent used herein may include solvents such asmethanol, ethanol, acetone or tetrahydrofuran, or mixed solventsconsisting of water and methanol, ethanol, acetone, tetrahydrofuran, orthe like.

[Step F-4]

This is a step of synthesizing compound (f-6) by using compound (f-5) asa raw material and applying the above production method ([Step 1-6]) or([Step 1-7]).

[Step F-5]

This is a step of synthesizing compound (2-1) by using compound (f-6) asa raw material and applying the above production method ([Step E3-2]).

[Step F-6]

This is a step of synthesizing compound (2-1) by using compound (f-7) asa raw material and applying the above production method ([Step 1-6]) or([Step 1-7]).[General Production Method G] (Synthesis Method of Compound (3-1))

wherein X′ and Z have the same meanings as described above; and Yrepresents a nitro group or amino group.

A commercially available product may directly be used as compound (g-1),or the above compound may also be produced from a commercially availableproduct by a method known to persons skilled in the art: Moreover, itcan also be produced by production examples in the present examples.

[Step G-1]

This is a step of obtaining compound (g-3) by the Sonogashira reactionof compound (g-1) with trimethylsilylacetylene (g-2). Sonogashirareaction is a synthesis method known to persons skilled in the art. Itcan be carried out under the same conditions as those described in, forexample, Erdelyi, M.; Gogoll, A.; J. Org. Chem., 66 (12), 4165-4169(2001)., Ezquerra, J.; Pedregal, C.; Lamas, C.; Barluenga, J.; Perez,M.; Garcia-Martin, M. A.; Gonzalez, J. M.; J. Org. Chem., 61 (17),5804-5812 (1996).

[Step G-2]

This is a step of obtaining compound (3-1) by subjecting compound (g-3)to a reduction reaction.

The reduction of a nitro group is a reaction known to persons skilled inthe art. As a reduction reaction performed in the presence of acetylene,a method of reducing a nitro group into an amino group using tin or zincunder acidic conditions is preferable. Moreover, a reduction with iron,which uses ammonium chloride under neutral conditions, is also applied.The reaction can be carried out under the same conditions as thosedescribed in, for example, Izumi, T.; Yokota, T.; J. Heterocycl. Chem.,29 (5), 1085-1090 (1992)., Hartman, W. W.; Dickey, J. B.; Stampfli, J.G.; Org. Synth., II, 175 (1943) (when Y is an amino group, however, thisstep does not need to be carried out).[Concerning Preparation of Compound (g-1)]

wherein Z has the same meaning as described above.

As described above, a commercially available product can directly beused as compound (g-1), or the above compound may also be produced froma commercially available product according to a method known to personsskilled in the art. Specifically, various ester compounds or an amidecompound as compound (g-1) can be synthesized from4-bromo-3-nitrobenzoic acid according to general methods known topersons skilled in the art.

[General Production Method H] (Synthesis Method of Compound (1-9))

This is a method for synthesizing compound (1-9), which differs fromGeneral production method E.

wherein each of ring A, R₍₁₎, R₍₄₎, R₍₅₎, R₍₆₎, R′₍₄₎, R′₍₅₎, and R′₍₆₎has the same meaning as described above; R₍₁₄₎ represents a hydrogenatom, a lower alkyl group such as a methyl group or ethyl group, or alower aralkyl group such as a benzyl group; X₍₁₎ represents a halogenatom such as a fluorine atom, chlorine atom, bromine atom, or iodineatom; P₍₂₎ represents a protecting group for an alcoholic hydroxylgroup, such as an acyl group or benzoyl group; and P₍₃₎ represents aprotecting group for a phenolic hydroxyl group, such as a methoxymethylgroup, 1-ethoxyethyl group, or tetrahydropyranyl group.[Step H-1]

A commercially available product may directly be used as compound (h-1),or the above compound may also be produced from a commercially availableproduct according to a method know to persons skilled in the art, suchas the method described in J. Velkov; Z. Mincheva; J. Bary; G. Boireau;C. Fujier; Synthetic Communications, 27 (3), 375-378 (1997).

This is a step of obtaining compound (h-2) by subjecting compound (h-1)to a reduction reaction, protecting an alcoholic hydroxyl group, andthen deprotecting the protecting group of a phenolic hydroxyl group.

The reduction reaction of an ester group can be carried out under thesame conditions as commonly used conditions described in, for example,the 4^(th) edition Jikken Kagaku Koza 26, pp. 159 to 266.

Examples of a reducing agent used in the reaction may include lithiumaluminum hydride, lithium borohydride, diisobutyl aluminum hydride, andsodium bis(2-methoxyethoxy)aluminum hydride. The reaction temperature isnot particularly limited. It is generally between −78° C. and asolvent-reflux temperature, and preferably between −78° C. and a roomtemperature. A solvent used in the reaction is not particularly limited,as long as it does not inhibit the reaction and dissolves a startingsubstance to a certain extent. Preferred examples of such a solvent mayinclude tetrahydrofuran, ether, dimethoxyethane, cyclopentyl methylether, toluene, and methylene chloride.

Such a reducing agent is used at a ratio between 1 and 3 equivalents,and preferably between 1 and 1.5 equivalents, with respect to compound(h-1).

Introduction of a protecting group into an alcoholic hydroxyl group canbe carried out under the same conditions as commonly used conditionsdescribed in publications such as T. W. Green and P. G. M. Wuts,“Protective groups in Organic Chemistry, Second Edition”, John Wiley &Sons, Inc.

In the present reaction, when an alcoholic hydroxyl group is protectedby a benzoyl group for example, benzoyl chloride is allowed to reactwith the above alcohol form in the presence of a base such astriethylamine in a solvent such as toluene, xylene, ethyl acetate orether solvent such as dimethoxyethane or cyclopentyl methyl ether, so asto obtain a product of interest. Benzoyl chloride can be used at a ratiobetween 1 equivalent and an excessive amount with respect to thecompound alcohol form. Triethylamine can be used at a ratio between 1equivalent and an excessive amount with respect to the compound alcoholform. There may be cases where preferred results such as the improvementof yield or the reduction of the reaction time are obtained by thecoexistence of N,N,N,N-tetramethylethylenediamine,diisopropylethylamine, N,N-dimethylaniline, or the like, in the presentinvention.

The reaction time is not particularly limited. It is generally between0.5 and 48 hours, and preferably between 0.5 and 4 hours. The reactiontemperature is between 0° C. and 100° C., and preferably between 0° C.and a room temperature.

Deprotection of a protecting group for a phenolic hydroxyl group can becarried out under the same conditions as those described in publicationssuch as T. W. Green and P. G. M. Wuts, “Protective groups in OrganicChemistry, Second Edition”, John Wiley & Sons, Inc.

In the present reaction, when a phenolic hydroxyl group is protected bya methoxymethyl group, 1-ethoxyethyl group, or the like, the hydroxylgroup is allowed to react with hydrochloric acid in a mixed solventconsisting of toluene, dimethoxyethane, and tetrahydrofuran, so as toobtain compound (h-2). The amount of hydrochloric acid used is between 1equivalent and an excessive amount with respect to a starting substance.The reaction time is not particularly limited. It is generally between0.5 and 48 hours, and preferably between 1 and 4 hours. The reactiontemperature is between 0° C. and 100° C., and preferably between 0° C.and a room temperature.

[Step H-2]

This is a step of obtaining compound (h-4) by allowing a phenoliccompound to react with 3,3-dimethylacryloyl acid or a3,3-dimethylacryloyl acid derivative such as 3,3-dimethylaclyloylchloride.

The reaction can be carried out under the same conditions as thosedescribed in publications such as T. Timar et al., “Synthesis of2,2-Dimethyl-4-Chromanones”, J. Heterocyclic Chem., 37, 1389 (2000), J.C. Jaszberenyi et al., “On the Synthesis of Substituted2,2-Dimethyl-4-Chromanones and Related Compound” Tetrahedron Letters, 30(20), 2791-2794, (1992), J. C. Jaszberenyi et al., Heterocycles, 38 (9),2099, (1994). Other than these methods, compound (h-4) can also beobtained by allowing compound (h-2) to react with 3,3-dimethylacryloylacid in the presence of methanesulfonic acid. 3,3-dimethylacryloyl acidis used at a ratio between 1 equivalent and an excessive amount withrespect to compound (h-2). The reaction time is not particularlylimited. It is generally between 0.5 and 48 hours, and preferablybetween 1 and 4 hours.

The reaction temperature is between a room temperature and 100° C., andpreferably between 40° C. and 60° C.

[Step H-3]

This is a step of obtaining compound (1-9) by deprotecting an alcoholichydroxyl group of compound (h-4) and then oxidizing the obtained alcoholcompound.

The reaction can be carried out under the same conditions as thosecommonly used for deprotection of a protecting group for an alcoholichydroxyl group described in publications such as T. W. Green and P. G.M. Wuts, “Protective groups in Organic Chemistry, Second Edition”, JohnWiley & Sons, Inc. For example, an alcoholic hydroxyl group protected bya benzoate ester group or the like in compound (h-4) is allowed to reactwith 2N—NaOH or the like in an organic solvent such as tetrahydrofuran,methanol or ethanol, or in a mixed solvent thereof, so as to obtain aproduct of interest. 2N—NaOH is used at a ratio between 1 equivalent andan excessive amount with respect to compound. (h-4). The reaction timeis not particularly limited. It is generally between 0.5 and 48 hours,and preferably between 1 and 5 hours.

The reaction temperature is between 0° C. and 100° C., and preferablybetween a room temperature and 50° C.

The following reaction involves a step of obtaining compound (1-9) bysubjecting the thus obtained compound having an alcoholic hydroxyl groupto an oxidation reaction.

An aldehyde compound can be obtained from an alcohol compound accordingto a method known to persons skilled in the art.

Examples of a known oxidation method used in the present reaction mayinclude Swern oxidation, Corey-Kim oxidation, Moffatt oxidation, PCCoxidation, PDC oxidation, Dess-Martin oxidation, SO₃-pyridine oxidation,and TEMPO oxidation.

A solvent used in the reaction is not particularly limited, as long asit does not inhibit the reaction and dissolves a starting substance to acertain extent. Examples of such a solvent may include dimethylsulfoxide, tetrahydrofuran, toluene, methylene chloride, chloroform,ethyl acetate, water, and a mixed solvent thereof.

An oxidizing agent is used at a ratio between a catalytic amount and anexcessive amount with respect to an alcohol form.

The reaction temperature is not particularly limited. It is generallybetween −78° C. and a solvent-reflux temperature, and preferably between−5° C. and a room temperature. The reaction time is not particularlylimited. It is generally between 3 and 10 hours, and preferably between3 and 5 hours.

In the case of TEMPO oxidation for example, it can be carried outaccording to the method described in Jikken Kagaku Koza 23, Yuki GoseiV, Sanka Hanno Maruzen Co., Ltd., pp. 485-513.

A solvent used in the reaction is not particularly limited, as long asit does not inhibit the reaction and dissolves a starting substance to acertain extent. Examples of such a solvent may include dimethylsulfoxide, tetrahydrofuran, toluene, methylene chloride, chloroform,ethyl acetate, water, and a mixed solvent thereof.

An oxidizing agent, for example, sodium hypochlorite contained in asodium bicarbonate aqueous solution, is used at a ratio between acatalytic amount and an excessive amount with respect to an alcohol formin the presence of 2,2,6,6-tetramethylpiperidinooxy-sodium bromide.

The reaction temperature is not particularly limited. It is generallybetween −20° C. and a room temperature, and preferably between −5° C.and a room temperature. The reaction time is not particularly limited.It is generally between 3 and 10 hours, and preferably between 3 and 5hours.

In the case of Swern oxidation for example, it can be carried outaccording to the method described in Jikken Kagaku Koza 23, Yuki GoseiV, Sanka Hanno, Maruzen Co., Ltd., pp. 369-403.

A solvent used in the reaction is not particularly limited, as long asit does not inhibit the reaction and dissolves a starting substance to acertain extent. Examples of such a solvent may include dimethylsulfoxide, tetrahydrofuran, toluene, methylene chloride, chloroform,ethyl acetate, and a mixed solvent thereof.

As an oxidizing agent acting as an activator of dimethyl sulfoxide,oxalyl chloride, trifluoroacetic anhydride, acetic anhydride,cyclohexylimide, diphosphorus pentoxide, or the like is used at a ratiobetween a two-times molar amount and an excessive amount with respect toan alcohol form.

As a base, triethylamine, N,N-diisopropylethylamine, pyridine, or thelike is used at a ratio between a two-times molar amount and anexcessive amount with respect to an alcohol form.

The reaction temperature is not particularly limited. It is generallybetween −70° C. and a room temperature. The reaction time is generallybetween 3 and 10 hours, and preferably between 3 and 5 hours.

An aldehyde compound (1-9) can simply be purified by converting it intoa sodium bisulfite adduct according to the method described in D. P.Kjell et al., “A Novel, Nonaqueous Method for Regeneration of Aldehydesfrom Bisulfite Adducts” J. Organic. Chemistry. 64, 5722-5724 (1999). Inaddition, aldehyde can also easily be regenerated. A sodium bisulfiteadduct can be obtained by allowing an aldehyde form (1-9) to react witha sodium bisulfite aqueous solution for example, in an organic solventsuch as ethanol, ethyl acetate or methanol, or in a mixed solventthereof. Such sodium bisulfite is used at a ratio between 1 equivalentand an excessive amount with respect to compound (1-9). The reactiontemperature is not particularly limited. It is generally between 10° C.and 40° C., and preferably a room temperature. The reaction time isgenerally between 1 and 48 hours, and preferably between 12 and 24hours.

The thus obtained sodium bisulfite adduct is treated with a base such aspotassium carbonate, sodium carbonate, sodium hydroxide, or potassiumhydroxide, in an organic solvent such as ethanol, ethyl acetate, ormethanol, or in a mixed solvent thereof, so as to obtain an aldehydeform (1-9). A base is used at a ratio between 1 equivalent and anexcessive amount with respect to the sodium bisulfite adduct. Thereaction temperature is not particularly limited. It is generallybetween 10° C. and 40° C., and preferably a room temperature. Thereaction time is generally between 1 and 24 hours, and preferablybetween 1 and 2 hours.

Compound (1-9) can be used to produce the compound represented byformula (I), with or without purification.

In order to demonstrate the usefulness of the compound represented bygeneral formula (I) of the present invention, the present inventors haveconducted the following tests.

The test examples and reference examples indicated below are providedfor illustrative purposes only. Thus, the agent of the present inventionfor treating or preventing lower urinary tract symptoms is not limitedto these examples in any case. Persons skilled in the art can realizethe present invention to the maximum, not only by using the testexamples and reference examples indicated below, but also by addingvarious modifications to the scope of claims in the specification of thepresent application. Such modifications are included in the scope ofclaims in the specification of the present application.

TEST EXAMPLE 1

[Test Regarding Affinity for Serotonin 1A Receptor]

(1) The affinity of a test substance for a 5-HT1A receptor was examinedby an inhibition experiment, in which the inhibitory effect of the testsubstance against the binding of[³H]-4-(2′-methoxy)phenyl-1-(2′-(N-2″-pyridinyl)-p-fluorobenzamido)ethyl-piperazine(MPPF) that selectively binds to the 5-HT1A receptor in a swinehippocampal membrane fraction was examined. The 5-HT1A receptor that isa G-protein binding receptor becomes a G-protein binding state withaddition of MgCl₂. In contrast, it becomes a G-protein non-binding statewith addition of guanylylimido diphosphate (Gpp(NH)p). Generally, it hasbeen known that a G-protein receptor agonist exhibits strong affinityfor a receptor that is in a G-protein binding state, depending on thelevel of intrinsic activity thereof. Thus, both the affinity of a testsubstance to the receptor that was in a state of not binding to theG-protein and the affinity of the test substance to the receptor thatwas in a state of binding to the G-protein were obtained. Then, theobtained values were compared to each other, so as to estimate the levelof the intrinsic activity of the test substance. Theoretically, when thevalue (L/H) obtained by dividing the affinity of a test substance to thereceptor that is in a low affinity state (IC50 value) by the affinity ofa test substance to the receptor that is in a high affinity state (IC50value) is 1 or less, the intrinsic activity thereof is zero. The greaterthis value, the higher the intrinsic activity that can be obtained.Actually, it was judged that a test substance had no intrinsic activitywhen it had an L/H value of 1 or smaller, and that the test substancehad intrinsic activity when it had an L/H value of 2 or greater.

Swine hippocampus was homogenized in a 50 mM Tris-Hcl buffer (pH 7.4;hereinafter referred to as buffer A) that had been cooled on ice. Thesuspension was centrifuged at 40,000×g for 15 minutes. The obtainedpellet was suspended in buffer solution A, and the thus obtainedsolution was then centrifuged at 40,000×g for 15 minutes. The sameoperation was repeated 2 or 3 times. The finally obtained pellet wassuspended in a buffer solution A in an amount 10 times the wet weight ofthe swine hippocampus, so as to obtain a membrane fraction. The obtainedmembrane fraction was stored at −80° C. until use.

A mixture (0.5 ml) used for incubation comprised an appropriate amountof the membrane fraction, a test substance with a desired concentration,MgCl₂ (final concentration: 10 mM) or Gpp(NH)p (final concentration: 1mM), [³H]MPPF (final concentration: 0.5 nM), dimethyl sulfoxide (finalconcentration: 1% (v/v)), and a 50 mM Tris-Hcl buffer (pH 7.4). Thereaction was initiated with addition of the membrane fraction, and themixture was incubated at 37° C. for 30 minutes. After completion of theincubation, the mixture was subjected to vacuum filtration with a glassfilter, using Cell Harvester. The filter was washed with buffer solutionA that had been cooled on ice. Thereafter, radioactivity binding to thereceptor was measured with a liquid scintillation counter. Non-specificbinding was defined as binding detected in the presence of 10 μMWAY-100,635. The following Table 1 shows data regarding affinity thatare indicated by IC50 values obtained from an inhibition curve.

(2) Results

The compound of the present invention, a salt thereof, or a hydratethereof exhibited superior receptor binding action. It is to be notedthat compound A indicates the compound described in Example 337 ofWO98/43956. TABLE 1 Test substance Low affinity High affinity CompoundNo. IC50 (nM) IC50 (nM) L/H ratio Compound A 0.5 0.1 3.7  1 0.26 0.161.6  2 0.35 0.27 1.3  3 0.34 0.46 0.7  4 0.15 0.17 0.9  5 0.45 0.57 0.8 6 0.2 0.2 1  7 0.3 0.41 0.7  8 0.23 0.22 1  9 0.13 0.17 0.8 15 0.610.72 0.8 19 0.69 1.1 0.6 20 0.16 0.2 0.8 22 0.1 0.13 0.8 24 0.17 0.220.8 25 0.16 0.18 0.9 26 0.2 0.16 1.3 27 0.26 0.23 1.1 28 0.19 0.14 1.430 0.19 0.2 1 Compound A 0.5 0.1 3.7 31 0.15 0.16 0.9 32 0.25 0.26 1 330.12 0.17 0.7 34 0.2 0.26 0.8 35 0.23 0.27 0.9 36 0.14 0.26 0.5 37 0.390.55 0.7 38 0.13 0.2 0.7 44 0.47 0.4 1.2 45 0.69 0.58 1.2 46 0.33 0.241.4 47 0.23 0.23 1 48 1.1 1.2 0.9 49 0.27 0.22 1.2 51 0.17 0.18 0.9 520.2 0.22 0.9 53 0.46 0.31 1.5 54 0.13 0.18 0.7 57 0.24 0.18 1.3 58 0.390.33 1.2 59 0.12 0.19 0.6 60 0.24 0.28 0.9 Compound A 0.5 0.1 3.7 11 0.10.22 0.4 12 0.16 0.17 0.9 13 0.22 0.32 0.7 14 0.34 0.46 0.7 16 0.17 0.180.9 29 0.3 0.34 0.9 39 0.09 0.13 0.7 40 0.17 0.18 0.9 41 0.14 0.2 0.7 430.15 0.22 0.7 50 0.21 0.21 1 56 0.04 0.07 0.5

TEST EXAMPLE 2

[Antagonistic Effect on a Serotonin 1A Receptor Agonist-InducedHypothermia in Mouse]

(1) A thermistor probe was inserted at a depth of approximately 2 cminto the rectum of CD-1 (ICR) male mice (25-45 g), so as to measure thebody temperature thereof. Body temperature is decreased by subcutaneousadministration of serotonin 1A receptor agonist(8-hydroxy-dipropylaminotetralin (8-OH-DPAT) 0;5 mg/kg. Since aserotonin 1A antagonist inhibits such action, the antagonistic effect ofa test substance to a serotonin 1A receptor was evaluated using theinhibitory effect of the hypothermia as an index. The test results areshown in Table 2 indicated below. A test substance was administered 15minutes before the administration of the serotonin 1A agonist. Aserotonin 1A partial agonist alone decreases the body temperature,depending on the degree of the agonistic action thereof. In addition, ithas a weak antagonistic effect on 8-OH-DPAT-induced hypothermia. Theresults are shown in Table 2.

(2) Results

The compound of the present invention, a salt thereof, or a hydratethereof exhibited a superior pharmacological effect. TABLE 2 Testsubstance ED50 Compound No. (mg/kg, sc). Compound A >1 1 0.3 2 0.4 30.18 4 0.1 5 0.24 6 0.35 7 0.38 8 0.07 9 0.3 20 0.03 22 0.1 24 0.3 250.1 26 0.25 27 0.42 28 0.02 30 0.62 31 0.04 32 0.04 33 0.12 34 0.37 350.2 36 0.2 38 0.19 44 0.41 45 0.26 46 0.3 47 0.21 48 0.06 49 0.28 510.66 52 0.5 53 0.3 54 0.84 57 0.1 58 0.53 59 0.3 60 0.52

TEST EXAMPLE 3

[Inhibitory Action Against the Accentuated Urinary Reflex Action of RatDue to Destruction of the Superior Colliculus thereof]

(1) In the present test, Sprague-Dawley female rates (200-350 g) wereused. The rats were subjected to median incision of the abdomen underanesthesia. Thereafter, a hole with a minor diameter was made on thehead portion of the bladder, and a catheter used for measurement of anintravesical pressure was placed therein. A catheter used foradministration of a test substance was placed in the femoral vein. Thesecatheters were fixed at the occipital region of the rat through thesubcutis. One day later, the urinary reflex of the rats was measuredwith a cystometrogram. Thereafter, the rats were fixed on a brainstereotaxis apparatus under anesthesia, and then subjected to medianincision of the scalp. Thereafter, a hole was created with a dentaldrill at the cranium in the upper portion of the superior colliculus inaccordance with the coordinate of a brain diagram. A microelectrode(diameter: 0.7 mm; length: 1.5 mm) of a legion generator was theninserted into the superior colliculus through the hole. Thereafter,electric current was applied (65° C., 4 minutes), so as to damage thebrain tissues. After completion of the operation, when the rat awakenedfrom anesthesia, cystometrogram was conducted again to confirm theenhanced state of urinary reflex. A test substance was administeredthrough the catheter placed in the femoral vein, and the action of thetest substance to the urinary reflex was evaluated. In addition, theeffects of several test substances were compared using the maximalreaction (Emax). The results are shown in Table 3.

(2) Results

The compound of the present invention, a salt thereof, or a hydratethereof exhibited superior pharmacological effects. TABLE 3 Testsubstance Dose Bladder capacity No. (mg/kg, iv) Emax (%) Compound A 0.01−36 3 0.03 62 4 0.03 107 20  0.3 94

TEST EXAMPLE 4

[Effect of Controlling Memory Disorder Induced by 8-OH-DPAT in Rats]

(1) A Sprague-Dawley male rats (130-200 g) were bred in an individualcage and used in the present test. For appetite stimulation, the bodyweight of the rats was reduced to approximately 80% of the originalweight by fasting. Thereafter, an increase in the body weight wascontinuously suppressed by restricted feeding. As a maze test, anelevated 8-arm radial maze (central platform diagonal length: 34 cm, armlength: 60 cm; arm width: 12 cm) was used. In order to allow the rats toremember the positions of baits placed on the arms, the rats were lefton the platform of the maze in which baits had been placed on the tipsof the 4 predetermined arms. Thereafter, the rats were left on the mazefor a certain period of time or until it ate all the baits. Thistraining was carried out 1 to 3 times a day. The rats that hadsufficiently learned were subjected to the following experiment. Asolvent or test substance was subcutaneously administered to the rats.Twenty minutes later, 0.5 mg/kg 8-OH-DPAT was subcutaneouslyadministered thereto. Further, 20 minutes later, the same maze test asthat in the training was carried out. A reference memory error wasdefined as an action to enter arms on which no baits had been placed,and a working memory error was defined as an action to enter again armson which baits had previously been placed. Thus, the actions of the ratwere recorded. In addition, the time required for the rat to take allthe four baits was also recorded. When the rat did not take all the fourbaits within a certain period of time, the test was terminated at thattime, and the required time was defined as an elapsed time.(Reference:Yoshihiro Hiraga, “Effects of scopolamine upon delayedradial-arm maze performance in rats” Folia pharmacol. Japon. 97, 351-359(1991)) The results are shown in Table 4.

(2) Results

The compound of the present invention, a salt thereof, or a hydratethereof exhibited superior pharmacological effect. TABLE 4 Number ofNumber of Elapsed working reference time memory errors memory errors(second) N Solvent 7.13 ± 1.01 2.63 ± 0.63 371 ± 44.8 8 (1 mL/kg, s.c.)Test compound 0.25 ± 0.16 1.50 ± 0.57 52 ± 9.9 8 No. 20 (0.3 mg/kg,s.c.)Mean ± S.E.

TEST EXAMPLE 5

[Evaluation of Antianxiety Effect by Mouse Light/Dark Box Test]

(1) The method of Belzung C., Misslin R., and Vogel E. (Reference:Behavioural effects of the benzodiazepine receptor partial agonistRO16-6028 in mice, Psychopharmacology, 97, 388-391, 1989) was modified.The present mouse light/dark box test was carried out according to sucha modified method. As a test device used in this test, a lidded blackacryl box (dark box, 15×10×20 cm) was connected to a lidless white acrylbox (light box, 15×20×20 cm) using a black-acryl tunnel (10×7×4.5 cm),so as to prepare a light/dark box in which a mouse can freely movebetween the dark box and the light box. In this test device, in order toobserve the behavior of the mouse, the anterior surface (20×20 cm) andback surface (20×20 cm) of the light box were made from transparentacryl. The illumination was set to provide in an illuminance of 150 Luxon the floor of the light box. Thereafter, each of male C57BL mice(20-35 g) was placed in the dark box, and the test was started. In thistest, a test substance was subcutaneously administered to the testanimal 30 minutes before the initiation of the test.

The behavior of the mice was observed for 5 minutes after the initiationof the test. A state where the 4 legs of the mouse were contacted withon the floor of the light box was defined as stay at a light place, andthe time when the mouse stayed at a light place was measured. Theobtained time was used as an index of antianxiety action. The resultsare shown in Table 5.

(2) Results

The compound of the present invention, a salt thereof, or a hydratethereof exhibited superior pharmacological effect. TABLE 5 Testsubstance Time of stay at Compound No. 20 light place (mg/kg, sc)(second) N solvent 39 ± 5.5 7 0.03 46 ± 9.4 7 0.1  67 ± 19  7

From the above results, it was found that the compound represented byformula (I) of the present invention that is a novel compound exhibitssuperior action and effects as a pharmaceutical and is useful as a novelagent for treating or preventing lower urinary tract symptoms, learningor memory disorder or anxiety disorder. That is to say, the agent fortreating and preventing lower urinary tract symptoms, learning or memorydisorder or anxiety disorder of the present invention is apharmaceutical, which contains, as an active ingredient, a compoundhaving affinity for a 5-HT1A receptor selectively and also havingantagonistic effect to the above receptors in the central nerve system,a salt thereof, or a hydrate thereof. It exerts particularly remarkableeffects of treating or preventing symptoms regarding urinary storage,such as frequent urination, urinary urgency, or urinary incontinence.

The term “salt” is used to mean a pharmacologically acceptable salt.Such a salt is not particularly limited, as long as it forms apharmacologically acceptable salt of the compound represented by generalformula (I) contained in a therapeutic or preventive agent for lowerurinary tract symptoms. Preferred examples of such a salt may includehalogenated hydroacid salts (e.g., hydrofluoride, hydrochloride,hydrobromate, and hydroiodide), inorganic acid salts (e.g., sulfate,nitrate, perchlorate, phosphate, carbonate, and bicarbonate), organiccarboxylates. (e.g., acetate, oxalate, maleate, tartrate, fumarate, andcitrate), organic sulfonates (e.g., methanesulfonate,trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate,toluenesulfonate, and, camphorsulfonate), amino acid salts (e.g.,aspartate and glutamate), quaternary amine salts, alkali metal salts(e.g., sodium salt and potassium salt), and alkali-earth metal salts(e.g., magnesium salt and calcium salt).

The therapeutic or preventive agent for lower urinary tract symptoms ofthe present invention can be formulated by common methods. Preferreddosage forms include a tablet, a powder, a parvule, a granule, a coatedtablet, a capsule, a syrup, a troche, an inhalant, a suppository, aninjection, an ointment, an eye drop, an eye ointment, a nasal drop, anear drop, a poultice, and a lotion. For formulation, commonly usedadditives may be used. Examples of such an additive may include anexcipient, a binder, a lubricant, a coloring agent, flavor, as well as,a stabilizer, an emulsifier, an adsorption enhancer, a surfactant, a pHregulator, an antiseptic, and antioxidant, as necessary. The abovedescribed agent can be formulated by mixing ingredients that arecommonly used as raw materials for pharmaceutical formulations accordingto common methods. Examples of such ingredients may include: animal orvegetable oils such as soybean oil, tallow, or synthetic glyceride;hydrocarbons such as liquid paraffin, squalane, or solid paraffin; esteroils such as octyldodecyl myristate or isopropyl myristate; higheralcohols such as cetostearyl alcohol or behenyl alcohol; siliconeresins; silicone oils, surfactants such as polyoxyethylene fatty acidester, sorbitan fatty acid ester, glycerin fatty acid ester,polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenatedcastor oil, or a polyoxyethylene-polyoxypropylene block copolymer; watersoluble polymers such as hydroxyethyl cellulose, polyacrylic acid, acarboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, ormethyl cellulose; lower alcohols such as ethanol or isopropanol;polyvalent alcohols such as glycerin, propylene glycol, dipropyleneglycol, or sorbitol; sugars such as glucose or sucrose; inorganicpowders such as silicic acid anhydride, magnesium aluminum silicate, oraluminum silicate; and purified water. Examples of an excipient mayinclude lactose, corn starch, saccharose, glucose, mannitol, sorbit,crystalline cellulose, and silicon dioxide. Examples of a binder mayinclude polyvinyl alcohol, polyvinyl ether, methylcellulose,ethylcellulose, gum Arabic, Tragacanth, gelatin, shellac,hydroxypropylmethylcellulose, hydroxypropylcellulose,polyvinylpyrrolidone, a polypropylene glycol-polyoxyethylene blockpolymer, and meglumine. Examples of a disintegrant may include starch,agar, gelatin powder, crystalline cellulose, calcium carbonate, sodiumbicarbonate, calcium citrate, dextrin, pectin, andcarboxymethylcellulose calcium. Examples of a lubricant may includemagnesium stearate, talc, polyethylene glycol, silica, and hydrogenatedvegetable oil. As a coloring agent, products that are allowed foraddition to pharmaceuticals are used. Examples of flavor used herein mayinclude cocoa powder, menthol, aromatic powder, peppermint oil, borneol,and cinnamon powder.

In the case of an oral formulation, for example, a compound as an activeingredient, a salt thereof, or a hydrate thereof is mixed with anexcipient. In addition, a binder, a disintegrant, a lubricant, acoloring agent, flavor, or the like is added thereto, as necessary.Thereafter, the thus obtained mixture is formulated into a powder, afine granule, a granule, a tablet, a coated tablet, a capsule, or thelike, according to common methods. In the case of a tablet or granule,these formulations are naturally appropriately coated with sugar orother materials, as necessary. In the case of a syrup or a formulationused for injection, a pH regulator, a resolvent, an isotonizing agentare added, and as necessary, a solubilizer, a stabilizer, and the likeare also added. Thereafter, the obtained mixture is formulated accordingto common methods. In the case of an external preparation, theproduction method thereof is not limited, and the external preparationcan be produced by common methods. Various materials that are commonlyused for pharmaceuticals, quasi drugs, cosmetics, or the like, can beused herein as base materials. Examples of such a material may includeanimal and vegetable oils, mineral oils, ester oils, waxes, higheralcohols, fatty acids, silicone oils, surfactants, phospholipids,alcohols, polyvalent alcohols, water soluble polymers, clay minerals,and purified water. In addition, a pH regulator, an antioxidant, achelating agent, antiseptic and antifungal agents, a coloring agent, aperfume, or the like may also be added, as necessary. Moreover,components having differentiation-inducing action, such as a bloodflow-promoting agent, an antibacterial agent, an antiphlogistic, a cellactivator, vitamins, amino acid, a moisturizer, or keratolytic drug mayalso be added, as necessary. The dosage of the therapeutic or preventiveagent of the present invention is different depending on the degree ofsymptoms, age, sex, body weight, dosage form, the type of salts,specific type of disease, or the like. In general, the pharmaceutical isorally administered once or divided over several administrations perday, at a dosage approximately between 30 μg and 10 g, preferablybetween 100 μg and 5 g, and more preferably between 100 μg and 100 mg toadults. When the pharmaceutical is administered by injection, it isadministered once or divided over several administrations per day, at adosage approximately between 30 μg and 1 g, preferably between 100 μgand 500 mg, and more preferably between 100 μg and 30 mg to adults.

The present invention will be described more in detail in the referenceexamples and examples indicated below. The examples are provided forillustrative purposes only, and are not intended to limit the scope ofthe invention. The therapeutic or preventive agent for lower urinarytract symptoms of the present invention is a pharmaceutical, whichcontains, as an active ingredient, a compound having affinity for a5-HT1A receptor selectively and also having antagonistic effect to theabove receptor in the central nerve system, a salt thereof, or a hydratethereof. Persons skilled in the art can realize the present invention tothe maximum, not only by using the reference examples and examplesindicated below, but also by adding various modifications to the scopeof claims in the specification of the present application. Suchmodifications are included in the scope of claims in the specificationof the present application.

PRODUCTION EXAMPLE 1 Synthesis of1-(piperidin-4-yl)-1H-indole-6-carboxamide

(1) Synthesis of methyl1-(1-benzyloxycarbonylpiperidin-4-yl)-1H-indole-6-carboxylate

44.3 g of methyl 3-amino-4-(2,2-dimethoxyethyl)benzoate synthesizedaccording to the publication (Tetrahedron Letters, Vol. 37, No. 34, pp.6045-6048) and 64.9 g of benzyl 4-oxo-1-piperidinecarboxylate weredissolved in 485 ml of acetic acid, followed by stirring at roomtemperature. Approximately 20 minutes later, 58.9 g of sodiumtriacetoxyborohydride was added to the reaction solution. Then, thereaction solution was further stirred for 2 hours. Thereafter, 485 ml ofwater was added to the reaction solution, and the obtained mixture washeated to a temperature between 100° C. and 115° C. Approximately 3hours later, the reaction solution was cooled, and then concentratedunder a reduced pressure. Thereafter, water and ethyl acetate were addedthereto, so as to separate an organic layer. The obtained organic layerwas washed with a saturated sodium bicarbonate aqueous solution and asaturated sodium chloride solution, and dried over anhydrous magnesiumsulfate. After removing the drying agent by filtration, the organiclayer was concentrated under a reduced pressure, and the residue wasthen purified by NH silica gel column chromatography (hexane/ethylacetate). The obtained solid was suspended in a mixed solvent consistingof hexane and t-butylmethyl ether, followed by filtration, so as toobtain 64.6 g of the subject compound.

¹H-NMR (CDCl₃) δ 1.80-2.05 (m, 2H), 2.05-2.23 (m, 2H), 2.92-3.15 (m,2H), 3.96 (s, 3H), 4.30-4.60 (m, 3H), 5.18 (s, 2H), 6.58 (dd, J =0.4,2.8 Hz, 1H), 7.30-7.45 (m, 6H), 7.64 (dd, J=0.4, 8.4 Hz, 1H), 7.80 (dd,J=1.6, 8.4 Hz, 1H), 8.14 (s, 1H).

(2) Synthesis of1-(1-benzyloxycarbonylpiperidin-4-yl)-1H-indole-6-carboxylic acid

90.0 g of methyl1-(1-benzyloxycarbonylpiperidin-4-yl)-1H-indole-6-carboxylate wasdissolved in a mixed solution consisting of 760 ml of methanol and 200ml of tetrahydrofuran. Thereafter, 92 ml of a 5 N sodium hydroxideaqueous solution was added to the reaction solution, and the mixture wasthen heated to a temperature between 60° C. and 70° C. After completionof the reaction, the reaction solution was cooled, and 65.0 g ofammonium chloride was added thereto, followed by concentration under areduced pressure. A 5% KHSO₄ aqueous solution was added to the residue,so as to adjust pH to be 5 to 6, followed by extraction with ethylacetate. The organic layer was washed with water and a saturated sodiumchloride solution, and then dried over anhydrous magnesium sulfate.After removing the drying agent by filtration, the organic layer wasconcentrated under a reduced pressure. Thereafter, the residue wassolidified, and then collected from a mixed solvent consisting of hexaneand t-butylmethyl ether by filtration, so as to obtain 75.6 g of thesubject compound.

1H-NMR (CDCl₃) δ 1.80-2.04 (m, 2H), 2.06-2.21 (m, 2H), 2.94-3.16 (m,2H), 4.30-4.58 (m, 3H), 5.19 (s, 2H), 6.60 (dd, J=0.8, 3.6 Hz, 1H),7.30-7.44 (m, 6H), 7.68 (dd, J=0.8, 8.4 Hz, 1H), 7.88 (dd, J=1.6, 8.4Hz, 1H), 8.22 (s, 1H).

(3) Synthesis of benzyl4-(6-carbamoyl-1H-indol-1-yl)piperidin-1-carboxylate

75.0 g of 1-(1-benzyloxycarbonylpiperidin-4-yl)-1H-indole-6-carboxylicacid was dissolved in 620 ml of tetrahydrofuran. Thereafter, 38.6 g of1,1′-carbonylbis-1H-imidazole was added thereto. The reaction solutionwas stirred at room temperature for 1.5 hours, and 134 ml of a 28%ammonium water was then added thereto. After completion of the reaction,the reaction solution was concentrated under a reduced pressure, andthen extracted with ethyl acetate. The obtained organic layer was washedwith a saturated sodium chloride solution and a saturated ammoniumchloride aqueous solution. Tetrahydrofuran was added to the separatedorganic layer, and a partially solidified subject compound was dissolvedtherein, followed by drying over anhydrous magnesium sulfate. Afterremoving the drying agent by filtration, the organic layer wasconcentrated under a reduced pressure. The solidified subject compoundwas collected by filtration. The thus collected subject compound wassuspended in tetrahydrofuran, and the mixture was heated, followed byfiltration. The thus collected subject compound was then suspended in amixed solvent consisting of tetrahydrofuran and methanol, and theobtained mixture was heated, followed by filtration. The generatedfiltrates were gathered and concentrated, and thus, the subject compoundwas obtained in the same above manner. The total amount of the subjectcompounds was 64.8 g.

¹H-NMR (CDCl₃) δ 1.93 (brs, 2H), 2.04-2.18 (m, 2H), 3.02 (brs, 2H),4.26-4.60 (m, 3H), 5.18 (s, 2H), 6.58 (dd, J=0.8, 3.2 Hz, 1H), 7.28-7.44(m, 7H), 7.65 (dd, J=0.4, 8.4 Hz, 1H), 8.10 (s, 1H).

(4) Synthesis of 1-(piperidin-4-yl)-1H-indole-6-carboxamide

43 g of benzyl 4-(6-carbamoyl-1H-indol-1-yl)piperidin-1-carboxylate wassuspended in a mixed solution consisting of 400 ml of methanol and 600ml of tetrahydrofuran. Thereafter, 3.3 g of 10% palladium carbon wasadded thereto. This suspension was substituted by hydrogen, and it wasthen stirred at room temperature. After completion of the reaction, 10%palladium carbon was filtered off from the reaction solution, and thereaction solution was then concentrated under a reduced pressure.Tetrahydrofuran was added to the residue, and the obtained mixture wasconcentrated again under a reduced pressure. Tetrahydrofuran was addedto the generated residue, followed by stirring, so as to solidify thesubject compound. Thereafter, tetrahydrofuran and ether were addedthereto, followed by cooling on ice. The solidified subject compound wascollected by filtration. The generated filtrate was concentrated, andthus, the subject compound was obtained in the same above manner. Thetotal amount of the subject compounds was 25.2 g.

¹H-NMR (CDCl₃) δ 1.88-2.02 (m, 2H), 2.06-2.16 (m, 2H), 2.80-2.92 (m,2H), 3.22-3.32 (m, 2H), 4.46 (tt, J=4.0, 12.0 Hz 1H), 6.58 (dd, J=0.8,3.2 Hz, 1H), 7.36-7.44 (m, 2H), 7.65 (d, J=8.4 Hz, 1H), 8.11 (s, 1H).

PRODUCTION EXAMPLE 2 Synthesis ofN-methyl-1-(piperidin-4-yl)-1H-indole-6-carboxamide

(1) Synthesis ofN-methyl-1-(1-benzyloxycarbonylpiperidin-4-yl)-1H-indole-6-carboxamide

2.00 g of 1-(1-benzyloxycarbonylpiperidin-4-yl)-1H-indole-6-carboxylicacid was dissolved in 20 ml of tetrahydrofuran, and 1.03 g of1,1′-carbonylbis-1H-imidazole was then added thereto. The obtainedmixture was stirred at room temperature for 1.5 hours, and 4.11 ml of a40% methylamine aqueous solution was added thereto. After completion ofthe reaction, the reaction solution was extracted with ethyl acetate.The organic layer was washed with a saturated sodium bicarbonate aqueoussolution, a saturated ammonium chloride aqueous solution, and asaturated sodium chloride solution. Thereafter, the organic layer wasdried over anhydrous magnesium sulfate. After removing the drying agentby filtration, the organic layer was concentrated under a reducedpressure, and the residue was then purified by NH silica gel columnchromatography (ethyl acetate) and silica gel column chromatography(hexane/ethyl acetate), so as to obtain 1.77 g of the subject compound.

H-NMR (CDCl₃) δ 1.80-2.00 (m, 2H), 2.03-2.17 (m, 2H), 2.90-3.10 (m, 2H),3.06 (d, J=4.8 Hz, 3H), 4.30-4.58 (m, 3H), 5.16 (s, 2H), 6.21 (brs, 1H),6.55 (dd, J=0.8, 3.2 Hz, 1H), 7.27 (d, J=3.6 Hz, 1H), 7.28-7.40 (m, 6H),7.61 (dd, J=0.8, 8.0 Hz, 1H), 8.03 (s, 1H).

(2) Synthesis of N-methyl-1-(piperidin-4-yl)-1H-indole-6-carboxamide

1.77 g ofN-methyl-l-(l-benzyloxycarbonylpiperidin-4-yl)-1H-indole-6-carboxamidewas dissolved in 30 ml of methanol. Then, 200 mg of 10% palladium carbonwas added to the obtained solution. The reaction atomosphere wasreplaced by hydrogen, and it was then stirred at room temperature. Aftercompletion of the reaction, 10% palladium carbon was filtered off fromthe reaction solution, and the reaction solution was then concentratedunder a reduced pressure. The residue was purified by NH silica gelcolumn chromatography (ethyl acetate/methanol), followed bysolidification from a mixed solution consisting of ethyl acetate,t-butylmethyl ether, and methanol, so as to obtain 973 mg of the subjectcompound.

¹H-NMR (CDCl₃) δ 1.86-1.99.(m, 2H), 2.06-2.14 (m, 2H), 2.84 (dt, J=2.4,12.4 Hz, 2H), 3.06 (d, J=4.8 Hz, 3H), 3.22-3.30 (m, 2H), 4.44 (tt,J=4.0, 12.0 Hz, 1H), 6.24 (brs, 1H), 6.54 (dd, J=0.8, 3.2 Hz, 1H),7.32-7.36 (m, 2H), 7.61 (dd, J=0.4, 8.4 Hz, 1H), 8.04 (s, 1H).

PRODUCTION EXAMPLE 3 Synthesis of3-amino-4-(2,2-dimethoxyethyl)benzamide

(1) Synthesis of 3-nitro-4-methylbenzamide

20.0 g of 3-nitro-4-methylbenzoic acid was dissolved in 400 ml oftetrahydrofuran. Thereafter, 21.5 g of 1,1′-carbonyldiimidazole and 0.1ml of dimethylformamide were added thereto. The obtained mixture wasstirred for 45 minutes. Thereafter, 20 ml of 28% ammonia water was addedthereto, followed by stirring at room temperature for 24 hours. Aftercompletion of the reaction, the reaction solution was concentrated undera reduced pressure, and the residue was separated into 600 ml of ethylacetate and 200 ml of water. The organic layer was separated, and thenwashed with 200 ml of 2 N hydrochloric acid, 100 ml of water, 100 ml ofa saturated sodium bicarbonate aqueous solution, and 100 ml of asaturated sodium chloride solution. It was then dried over anhydrousmagnesium sulfate. After removing the drying agent by filtration, thefiltrate was concentrated under a reduced pressure, so as to obtain 19.5of the subject compound.

¹H-NMR (CDCl₃) δ 2.67 (s, 3H), 7.47 (d, J=7.6 Hz 1H), 7.98 (dd, J=2.0Hz, 1H), 8.40 (d, J=2.0 Hz, 1H).

(2). Synthesis of 3-amino-4-(2,2-dimethoxyethyl)benzamide

19.5 g of 3-nitro-4-methylbenzamide and 30 g of dimethylformamidedimethyl acetal were dissolved in 200 ml of dimethylformamide. Theobtained mixture was stirred at 140° C. for 20 hours. The mixture wasthen concentrated under a reduced pressure. Thereafter, 360 ml ofmethanol and 25 g of chlorotrimethylsilane were added to the residue.The obtained solution was heated to reflux for 16 hours. The reactionsolution was cooled and then concentrated under a reduced pressure.Water and ethyl acetate were added thereto, so as to divide an organiclayer. The organic layer was separated, and then washed with a saturatedsodium bicarbonate aqueous solution and a saturated sodium chloridesolution. It was then dried over anhydrous magnesium sulfate. Themixture was filtered through 100 g of a silica gel layer, and thenwashed with ethyl acetate. Thereafter, the filtrate was concentratedunder a reduced pressure. 0.9 g of 10% palladium carbon was added to 150ml of a methanol solution containing the obtained crude product, and themixture was intensively stirred in a hydrogen atmosphere. Aftercompletion of the reaction, the catalyst was removed by filtration, andthe filtrate was concentrated under a reduced pressure. The obtainedresidue was purified by NH silica gel column chromatography(hexane/ethyl acetate), so as to obtain 11.5 g of the subject compound.

¹H-NMR (CDCl₃) δ 2.90 (d, J=5.2 Hz, 2H), 3.38 (s, 6H), 4.16-4.24 (br,2H), 4.99 (t, J=5.2 Hz, 3H), 5.52-5.67 (br, 1H), 5.93-6.10 (br, 1H),7.07 (dd, J=1.6, 7.6 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 7.18 (d, J=1.6 Hz,1H).

EXAMPLE 1 Synthesis of1-{1-[2-(6-methoxy-3-methylbenz[d]isoxazol-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) 2′-Allyloxy-4′-methokyacetophenone

5.00 g of 2′-hydroxy-4′-methoxyacetophenone was dissolved in 40 ml ofN,N-dimethylformamide at room temperature. Thereafter, 4.16 g ofpotassium carbonate and 2.80 ml of allyl bromide were successively addedto the reaction solution. After the disappearance of materials had beenconfirmed, water and ethyl acetate were added to the reaction solution,so as to separate an organic layer. The obtained organic layer waswashed with water and a saturated sodium chloride aqueous solution, andthen dried over anhydrous magnesium sulfate. After removing the dryingagent by filtration, the organic layer was concentrated under a reducedpressure, and the residue was then purified by silica gel columnchromatography (hexane/ethyl acetate), so as to obtain 5.60 g of thesubject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.61 (s, 3H), 3.84 (s, 3H), 4.60-4.65 (m, 2H),5.30-5.37 (m, 1H), 5.41-5.49 (m, 1H), 6.01-6.18 (m, 1H), 6.44 (d, J=2.4Hz, 1H), 6.53 (dd, J=2.4, 8.8 Hz, 1H), 7.84 (d, J=8.8 Hz,. 1H).

(2) 3′-Allyl-2′-hydroxy-4′-methoxyacetophenone and5′-allyl-2′-hydroxy-4′-methoxyacetophenone

5.60 g of 2′-allyloxy-4′-methoxyacetophenone was dissolved in 10 ml ofN,N-diethylaniline. The reaction solution was heated to reflux undernitrogen atmosphere. Approximately 6 hours later, the reaction solutionwas stood to cool, and then, water and ethyl acetate were added thereto,so as to separate an organic layer. The obtained organic layer waswashed with 5 N hydrochloric acid and a saturated sodium chlorideaqueous solution, and then dried over anhydrous magnesium sulfate. Afterremoving the drying agent by filtration, the organic layer wasconcentrated under a reduced pressure, and the residue was then purifiedby silica gel column chromatography (hexane/ethyl acetate), so as toobtain 3.37 g of 3′-allyl-2′-hydroxy-4′-methoxyacetophenone and 1.07 gof 5′-allyl-2′-hydroxy-4′-methoxyacetophenone.3′-allyl-2′-hydroxy-4′-methoxyacetophenone

¹H-NMR (CDCl₃) δ (ppm): 2.57 (s, 3H), 3.35-3.50 (m, 2H), 3.89 (s, 3H),4.90-5.05 (m, 2H), 5.85-6.05 (m, 1H), 6.48 (d, J=8.8 Hz, 1H), 7.64 (d,J=8.8 Hz, 1H), 12.8 (s, 1H).

5′-Allyl-2′-hydroxy-4′-methoxyacetophenone

¹H-NMR (CDCl₃) δ (ppm): 2.55 (s, 3H), 3.24-3.32 (m, 2H), 3.86 (s, 3H),5.01-5.10 (m, 2H), 5.90-6.04 (m, 1H), 6.41 (s, 1H), 7.42 (s, 1H),12.7(s, 1H).

(3) 7-Allyl-6-methoxy-3-methylbenzo[d]isoxazole

3.37 g of 3′-allyl-2′-hydroxy-4′-methoxyacetophenone was dissolved in 55ml of ethanol. Thereafter, 2.61 g of hydroxylamine hydrochloride, 3.21 gof sodium acetate, and 13 ml of water were successively added to thereaction solution. The reaction solution was heated to reflux forapproximately 3.5 hours. Thereafter, 1.30 g of hydroxylaminehydrochloride and 1.6 g of sodium acetate were dissolved in 6 ml ofwater, and the obtained solution was added to the reaction solution. Thethus obtained reaction solution was further heated to reflux. After thedisappearance of materials had been confirmed, water and ethyl acetatewere added thereto, so as to separate an organic layer. The obtainedorganic layer was washed with water and a saturated sodium chlorideaqueous solution, and then dried over anhydrous magnesium sulfate. Afterremoving the drying agent by filtration, the organic layer wasconcentrated under a reduced pressure, so as to obtain 3.48 g of a crudeoxime derivative. The obtained oxime derivative and 6.95 g oftriphenylphosphine were dissolved in 150 ml of tetrahydrofuran (THF),and the obtained solution was cooled on ice. Thereafter, 5.22 ml ofdiisopropyl azodicarboxylate dissolved in 75 ml of THF was addeddropwise thereto. After completion of the dropping, the reactionsolution was warmed to a room temperature, it was then stirred forapproximately 15 hours. The reaction solution was concentrated under areduced pressure, and the residue was then purified by silica gel columnchromatography (hexane/ethyl acetate), so as to obtain 1.30 g of thesubject compound.

1H-NMR (CDCl₃) δ (ppm): 2.53 (s, 3H), 3.62-3.68 (m, 2H), 3.93 (s, 3H),4.97-5.13 (m, 2H), 5.92-6.10 (m, 1H), 6.95 (d, J=8.8 Hz, 1H), 7.42 (d,J=8.8 Hz, 1H).

(4)1-{1-[2-(6-methoxy-3-methylbenz[d]isoxazol-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

1.00 g of AD-mix-α (manufactured by Aldrich; hereinafter, the same canbe said for the same terms found in the present specification) wasdissolved in 5 ml of t-butanol and 5 ml of water. Thereafter, 180 mg of7-allyl-6-methoxy-3-methylbenzo[d]isoxazole dissolved in 2 ml oft-butanol was added thereto. The reaction solution was stirred at roomtemperature. After the disappearance of materials had been confirmed,1.20 g of sodium sulfite was added to the reaction solution, and theobtained mixture was stirred for approximately 3 hours. Water and ethylacetate were added to the reaction solution, so as to separate anorganic layer. The obtained organic layer was washed with a saturatedsodium chloride aqueous solution and then dried over anhydrous magnesiumsulfate. After removing the drying agent by filtration, the organiclayer was concentrated under a reduced pressure, so as to obtain 176 mgof a crude diol derivative. 176 mg of the obtained diol derivative wasdissolved in 9 ml of tetrahydrofuran and 3 ml of water, and then, 261 mgof sodium metaperiodate was added thereto. The obtained mixture wasvigorously stirred. After the disappearance of materials had beenconfirmed, water and ethyl acetate were added to the reaction solution,so as to separate an organic layer. The obtained organic layer waswashed with a saturated sodium chloride aqueous solution and then driedover anhydrous magnesium sulfate. After removing the drying agent byfiltration, the organic layer was concentrated under a reduced pressure,so as to obtain 121 mg of a crude aldehyde derivative.

121 mg of the above aldehyde derivative dissolved in 2 ml ofdichloromethane and 57 μl of acetic acid were successively added to 4 mlof dichloromethane containing 122 mg of1-(piperidin-4-yl)-1H-indole-6-carboxamide. The reaction solution wasthen stirred for 5 minutes. Thereafter, 159 mg of sodiumtriacetoxyborohydride was added to the reaction solution, and themixture was then stirred at room temperature for 8 hours. Thereafter, 5N HaOH, a saturated sodium chloride aqueous solution, and chloroformwere added to the reaction solution, so as to separate an organic layer.The obtained organic layer was washed with a saturated sodium chlorideaqueous solution and then dried over anhydrous magnesium sulfate. Afterremoving the drying agent by filtration, the organic layer wasconcentrated under a reduced pressure, and the residue was purified byNH silica gel column chromatography (ethyl acetate), so as to obtain 100mg of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.06-2.16 (m, 4H), 2.28-2.39 (m, 2H), 2.54 (s,3H), 2.70-2.78 (m, 2H), 3.11-3.19 (m, 2H), 3.23-3.31 (m, 2H), 3.95 (s,3H), 4.34-4.46 (m, 1H), 6.56 (d, J=3.2 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H),7.38-7.45 (m, 3H), 7.64 (d, J=8.4 Hz, 1H), 8.09 (s, 1H).

EXAMPLE 2 Synthesis of1-{1-[2-(6-methoxy-3-methylbenzo[d]isoxazol-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized using5′-allyl-2′-hydroxy-4′-methoxyacetophenone as a raw material accordingto the methods described in Example 1, (3)-(4).

¹H-NMR (CDCl₃) δ (ppm): 2.08-2.18 (m, 4H), 2.26-2.36 (m, 2H), 2.54 (s,3H), 2.62-2.70 (m, 2H), 2.90-2. 99 (m, 2H), 3.18-3.28 (m, 2H), 3.93 (s,3H), 4.36-4.48 (m, 1H), 6.58 (d, J=3.2 Hz, 1H), 6.97 (s, 1H), 7.35 (s,1H), 7.38-7.44 (m, 2H), 7.65 (d, J=8.4 Hz, 1H), 8.13 (s, 1H)

EXAMPLE 3 Synthesis of1-{1-[2-(6-methoxy-2-methylbenzoxazol-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) 2-Allyloxy-4-methoxynitrobenzene

1.88 g of 5-methoxy-2-nitrophenol was dissolved in 20 ml ofN,N-dimethylformamide. Thereafter, 1.53 g of potassium carbonate and1.03 ml of allyl bromide were successively added to the reactionsolution. After the disappearance of materials had been confirmed, waterand ethyl acetate were added to the reaction solution, so as to separatean organic layer. The obtained organic layer was washed with water and asaturated sodium chloride solution, and then dried over anhydrousmagnesium sulfate. After removing the drying agent by filtration, theorganic layer was concentrated under a reduced pressure, and the residuewas then purified by silica gel column chromatography (hexane/ethylacetate), so as to obtain 2.09 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 3.87 (s, 3H), 4.62-4.70 (m, 2H), 5.30-5.38 (m,1H), 5.50-5.58 (m, 1H), 6.00-6.12 (m, 1H), 6.48-6.56 (m, 2H), 8.00 (d,J=9.6 Hz, 1H).

(2) 2-Allyloxy-4-methoxyaniline

2.09 g of 2-allyloxy-4-methoxynitrobenzene was dissolved in 20 ml ofethanol, 5 ml of THF, and 4 ml of water. Thereafter, 4.27 g of ammoniumchloride and 2.23 g of iron were added to the reaction solution, and theobtained mixture was stirred while heating at 80° C. for 4 hours.Thereafter, 2 g of ammonium chloride, 1 g of iron, and 0.25 ml of 5 NHCl were added to the reaction solution, and the obtained mixture wasfurther stirred while heating for approximately 2 hours. The reactionsolution was stood to cool and then filtered through celite. A saturatedsodium bicarbonate aqueous solution and ethyl acetate were addedthereto, so as to separate an organic layer. The obtained organic layerwas washed with a saturated sodium chloride solution and then dried overanhydrous magnesium sulfate. After removing the drying agent byfiltration, the organic layer was concentrated under a reduced pressure,and the residue was then purified by NH silica gel column chromatography(hexane/ethyl acetate), so as to obtain 1.09 g of the subject compound.

1H-NMR (CDCl₃) δ (ppm): 3.74 (s, 3H), 4.52-4.58 (m, 2H), 5.25-5.32 (m,1H), 5.37-5.46 (m, 1H), 6.01-6.12 (m, 1H), 6.36 (dd, J=2.4, 8.4 Hz, 1H),6.46 (d, J=2.4 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H).

(3) 2′-Allyloxy-4′-methoxyacetanilide

3 mg of 4-(dimethylamino)pyridine and 1 ml of acetic anhydride weresuccessively added to 2 ml of pyridine containing 1.09 g of2-allyloxy-4-methoxyaniline, and the reaction solution was then stirredat room temperature. After the disappearance of the raw material hadbeen confirmed, 5 N HCl and ethyl acetate were added to the reactionsolution, so as to separate an organic layer. The obtained organic layerwas washed with a saturated sodium chloride solution and then dried overanhydrous magnesium sulfate. After removing the drying agent byfiltration, the organic layer was concentrated under a reduced pressure.The residue was then solidified from t-butyl methyl ether-hexane, so asto obtain 1.04 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.18 (s, 3H), 3.78 (s, 3H), 4.54-4.62 (m, 2H),5.30-5.45 (m, 2H), 6.00-6.12 (m, 1H), 6.45-6.52 (m, 2H), 7.54 (brd-s,1H), 8.22 (d, J=9.6 Hz, 1H)

(4) 7-Allyl-6-methoxy-2-methylbenzoxazole

1.04 g of 2′-allyloxy-4′-methoxyacetanilide was dissolved in 20 ml of1-methyl-2-pyrrolidone. The reaction solution was then stirred whileheating at 190° C. under nitrogen atmosphere. Eight hours later, thereaction solution was stood to cool. Thereafter, water and ethyl acetatewere added to the reaction solution, so as to separate an organic layer.The obtained organic layer was washed with a saturated sodium chloridesolution and then dried over anhydrous magnesium sulfate. After removingthe drying agent by filtration, the organic layer was concentrated undera reduced pressure, so as to obtain a product (1.01 g). The obtainedproduct was dissolved in 20 ml of acetic acid without purification, andthe obtained solution was stirred while heating at 135° C. Aftercompletion of the reaction, the reaction solution was stood to cool.Thereafter, the solvent was concentrated under a reduced pressure. 5 NNaOH and ethyl acetate were added to the residue, so as to separate anorganic layer. The obtained organic layer was washed with a saturatedsodium chloride solution and then dried over anhydrous magnesiumsulfate. After removing the drying agent by filtration, the organiclayer was concentrated under a reduced pressure. The residue was thenpurified by silica gel column chromatography (hexane/ethyl acetate), soas to obtain 371 mg of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.60 (s, 3H), 3.55-3.65 (m, 2H), 3.88 (s, 3H),4.95-5.10 (m, 2H), 5.95-6.10 (m, 1H), 6.89 (d, J=8.8 Hz, 1H), 7.43 (d,J=8.8 Hz, 1H).

(5)1-{1-[2-(6-methoxy-2-methylbenzoxazol-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was obtained from7-allyl-6-methoxy-2-methylbenzoxazole of Example 3, (4), according tothe method described in Example 1, (4).

¹H-NMR (CDCl₃) δ (ppm): 2.06-2.18 (m, 4H), 2.28-2.40 (m, 2H), 2.62 (s,3H), 2.68-2.77 (m, 2H), 3.06-3.16 (m, 2H), 3.22-3.32 (m, 2H), 3.90 (s,3H), 4.34-4.47 (m, 1H), 6.58 (dd, J=0.6, 3.2 Hz, 1H), 6.88 (d, J=8.4 Hz,1H), 7.38-7.46 (m, 3H), 7.67 (d, J=8.4 Hz, 1H), 8.12 (s, 1H).

EXAMPLE 4 Synthesis of1-{1-[2-(6-methoxy-2-methylbenzoxazol-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) 4′-Methoxy-2′-(3-methyl-2-butenyl)oxyacetophenone

20.7 g of potassium carbonate and 23.2 ml of 1-bromo-3-methyl-2-butenewere successively added to 300 ml of acetone containing 25 g of2′-hydroxy-4′-methoxyacetophenone. The reaction solution was then heatedto reflux. Approximately 6 hours later, 4.14 g of potassium carbonateand 4.63 ml of 1-bromo-3-methyl-2-butene were further added thereto, andthe obtained mixture was heated to reflux. Approximately 34 hours later,the reaction solution was stood to cool, and then, it was filteredthrough celite. The filtrate was concentrated under a reduced pressure,and the residue was then purified by silica gel column chromatography(hexane/ethyl acetate), so as to obtain the subject compound. Thereaction was further carried out using 2′-hydroxy-4′-methoxyacetophenone(25 g×2 times) under the above described conditions. The total amount ofthe subject compounds was 98.7 g.

¹H-NMR (CDCl₃) δ (ppm): 1.76 (d, J=0.8 Hz, 3H), 1.81 (d, J=0.8 Hz, 3H),2.58 (s, 3H), 3.85 (s, 3H), 4.59 (d, J=6.8 Hz, 2H), 5.47-5.55 (m, 1H),6.45 (d, J=2.4 Hz, 1H), 6.51 (dd, J=2.4, 8.8 Hz, 1H), 7.84 (d, J=8.8 Hz,1H).

(2) 2′-Hydroxy-4′-methoxy-5′-(3-methyl-2-butenyl)acetophenone

49.2 g of 4′-methoxy-2′-(3-methyl-2-butenyl)oxyacetophenone wasdissolved in 100 ml of N,N-diethylaniline. The reaction solution washeated to reflux under nitrogen atmosphere. 3 hours later, the reactionsolution was stood to cool, and then, 5 N hydrochloric acid (300 ml) andt-butylmethyl ether (1,000 ml) were added thereto, so as to separate anorganic layer. The obtained organic layer was washed with 5 Nhydrochloric acid (300 ml×2) and a saturated sodium chloride solution(500 ml), and then dried over anhydrous magnesium sulfate. Afterremoving the drying agent by filtration, the organic layer wasconcentrated under a reduced pressure, and the residue was then purifiedby silica gel column chromatography (hexane/ethyl acetate), so as toobtain the subject compound. The reaction was further carried out using4′-methoxy-2′-(3-methyl-2-butenyl)oxyacetophenone (49.0 g) under theabove described conditions. The total amount of the subject compoundswas 74.1 g.

¹H-NMR (CDCl₃) δ (ppm): 1.71 (d, J=0.8 Hz, 3H), 1.76 (d, J=1.2 Hz, 3H),2.54 (s, 3H), 3.22 (dd, J=0.4, 7.2 Hz, 2H), 3.86 (s, 3H), 5.21-5.29 (m,1H), 6.39 (s, 1H), 7.40 (d, J=0.8 Hz, 1H), 12.7 (s, 1H).

(3) 6-Methoxy-2-methyl-5-(3-methyl-2-butenyl)benzoxazole

74.1 g of 2′-hydroxy-4′-methoxy-5′-(3-methyl-2-butenyl)acetophenone wasdissolved in 900 ml of ethanol. Thereafter, 56.4 g of hydroxylaminehydrochloride and 69.2 g of sodium acetate dissolved in 315 ml of waterwere added thereto. The reaction solution was heated to reflux for 4hours. Thereafter, the reaction solution was stood to cool, and thenconcentrated under a reduced pressure. A saturated sodium chloridesolution (500 ml) and t-butyl methyl ether (1,000 ml) were added to theresidue, so as to separate an organic layer. The obtained organic layerwas washed with a saturated sodium chloride solution (500 ml×4), andthen dried over anhydrous magnesium sulfate. After removing the dryingagent by filtration, the organic layer was concentrated under a reducedpressure, so as to obtain 77.4 g of a crude oxime derivative. 77.4 g ofthe obtained oxime derivative was dissolved in a mixed solventconsisting of 225 ml of acetonitrile and 75 ml of N,N-dimethylacetamide.Thereafter, 31.6 ml of phosphorus oxychloride was added dropwise to thesolution for approximately 15 minutes, while cooling on ice. Aftercompletion of the addition, the reaction solution was stirred for 5minutes while cooling on ice, and was then warmed to a room temperature.The reaction solution was then stirred at room temperature forapproximately 50 minutes. Thereafter, the reaction solution was addeddropwise to a stirred mixed solution consisting of 1,500 ml of t-butylmethyl ether and 1,500 ml of ice water in which 56 g of sodium acetatehad been dissolved. The obtained organic layer was washed twice with amixed solution consisting of 120 ml of a 2 N sodium hydroxide solutionand 250 ml of a saturated sodium chloride solution, and then furtherwashed with a saturated sodium chloride solution (500 ml×4 times).Thereafter, the resultant product was dried over anhydrous magnesiumsulfate. After removing the drying agent by filtration, the organiclayer was concentrated under a reduced pressure, and the residue wasthen purified by NH silica gel column chromatography (hexane/ethylacetate). The resultant product was further purified by silica gelcolumn chromatography (hexane/ethyl acetate), so as to obtain 56.2 g ofthe subject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.71 (s, 3H), 1.75 (d, J=1.2 Hz, 3H), 2.58 (s,3H), 3.36 (dd, J=0.8, 7.2 Hz, 2H), 3.87 (s, 3H), 5.28-5.36 (m, 1H), 6.96(s, 1H), 7.38 (s, 1H).

(4)1-{1-[2-(6-methoxy-2-methylbenzoxazol-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

37.2 g of the subject compound was obtained from the above described6-methoxy-2-methyl-5-(3-methyl-2-butenyl)benzoxazole (44.7 g in totalfor 4 batches) according to the method described in Example 1, (4)(however, when a diol product was obtained, 1 equivalent ofmethanesulfonamide was added.)

37.2 g of the above described subject compound was recrystallized from360 ml of methanol, so as to obtain 34.1 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.00-2.24 (m, 4H), 2.24-2.40 (m, 2H), 2.60 (s,3H), 2.62-2.76 (m, 2H), 2.86-3.02 (m, 2H), 3.14-3.32 (m, 2H), 3.89 (s,3H), 4.34-4.46 (m, 1H), 6.57 (dd, J=0.8, 2.8 Hz, 1H), 6.99 (s, 1H),7.36-7.47 (m, 3H), 7.65 (dd, J=0.4, 8.4 Hz, 1H), 8.12 (s, 1H).

EXAMPLE 5 Synthesis of1-{1-[2-(2-ethyl-6-methylbenzoxazol-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) 2′-Hydroxy-4′-methoxypropiophenone

6.00 g of 2′,4′-dihydroxypropiophenone was dissolved in 70 ml ofacetone. Thereafter, 7.09 g of potassium carbonate and 3.03 ml of methyliodide were successively added to the reaction solution. The reactionsolution was then heated to reflux. Approximately 3 hours later, thereaction solution was stood to cool and then filtered. The filtrate wasconcentrated under a reduced pressure. A saturated sodium chloridesolution and ethyl acetate were added to the residue, so as to separatean organic layer. The obtained organic layer was washed with 2 Nhydrochloric acid and a saturated sodium chloride solution, and thendried over anhydrous magnesium sulfate. After removing the drying agentby filtration, the organic layer was concentrated under a reducedpressure. The residue was solidified from hexane-ethyl acetate, so as toobtain 5.64 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.23 (t, J=7.2 Hz, 3H), 2.95 (q, J=7.2 Hz, 2H),3.83 (s, 3H), 6.40-6.45 (m, 2H), 7.65 (dd, J=1.6.Hz, 8.0 Hz, 1H), 12.8(s, 1H).

(2)1-{1-[2-(2-Ethyl-6-methoxybenzoxazol-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized using, as a raw material,2′-hydroxy-4′-methoxypropiophenone obtained in Example 5, (1), accordingto the methods described in Example 4, (1)-(4) (however, allyl bromidewas used instead of 1-bromo-3-methyl-2-butene, and two types of isomersobtained by the subsequent Claisen rearrangement(3′-allyl-2′-hydroxy-4′-methoxypropiophenone and5′-allyl-2′-hydroxy-4′-methoxypropiophenone) were induced into thecompound in Example 5 and the compound in Example 6 described later,respectively).

¹H-NMR (CDCl₃) δ(ppm): 1.45 (t, J=7.6 Hz, 3H), 2.07-2.16 (m, 4H),2.28-2.37 (m, 2H), 2.68-2.76 (m, 2H), 2.94 (q, J=7.6 Hz, 2H), 3.06-3.14(m, 2H), 3.22-3.31 (m, 2H), 3.89 (s, 3H), 4.35-4.46 (m, 1H), 6.57 (d,J=2.8 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 7.37-7.42 (m, 2H), 7.44 (d, J=8.8Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 8.10 (s, 1H).

EXAMPLE 6 Synthesis of1-{1-[2-(2-ethyl-6-methoxybenzoxazol-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized using the above described5′-allyl-2′-hydroxy-4′-methoxypropiophenone as a raw material accordingto the synthesis methods described in Example 4, (3)-(4) (refer to thesynthesis method of Example 5).

¹H-NMR (CDCl₃) δ (ppm): 1.43 (t, J=7.6 Hz, 3H), 2.07-2.16 (m, 4H),2.24-2.34 (m, 2H), 2.62-2.69 (m, 2H), 2.88-2.96 (m, 4H), 3.17-3.26 (m,2H), 3.88 (s, 3H), 4.32-4.46 (m, 1H), 6.56 (dd, J=0.8, 3.2 Hz, 1H), 6.99(s, 1H), 7.37-7.42 (m, 2H), 7.44 (s, 1H), 7.63 (d, J=8.4 Hz, 1H), 8.09(s, 1H).

EXAMPLE 7 Synthesis of1-{1-[2-(5-methoxy-2-methylbenzoxazol-4-yl)ethyl]piperidin-4-yl)-1H-indole-6-carboxamide

(1) 5-Allyloxy-2-methylbenzoxazole

2.58 g of 5-hydroxy-2-methylbenzoxazole (publication: Synthesis, 1982,68-69) was dissolved in 15 ml of N,N-dimethylformamide and 15 ml ofacetonitrile. Thereafter, 2.39 g of potassium carbonate and 1.61 ml ofallyl bromide were successively added to the reaction solution.Approximately 6 hours later, water and ethyl acetate were added to thereaction solution, so as to separate an organic layer. The obtainedorganic layer was washed with water and a saturated sodium chloridesolution, and then dried over anhydrous magnesium sulfate. Afterremoving the drying agent by filtration, the organic layer wasconcentrated under a reduced pressure, and the residue was then purifiedby silica gel column chromatography (hexane/ethyl acetate), so as toobtain 2.78 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.61 (s, 3H), 4.53-4.58 (m, 2H), 5.26-5.32 (m,1H), 5.39-5.46 (m, 1H), 6.01-6.12 (m, 1H), 6.90 (dd, J=2.4, 8.8 Hz, 1H),7.14 (d, J=2.4 Hz, 1H), 7.33 (dd, J=0.4, 8.8 Hz, 1H).

(2) 4-Allyl-5-hydroxy-2-methylbenzoxazole

2.78 g of 5-allyloxy-2-methylbenzoxazole was stirred while heating at atemperature between 185° C. and 190° C. under nitrogen atmosphere.Approximately 5 hours later, the reaction solution was stood to cool.Thereafter, acetonitrile was added thereto for solidification, so as toobtain 1.44 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.61 (s, 3H), 3.72-3.79 (m, 2H), 5.06 (s, 1H),5.14-5.22 (m, 2H), 6.01-6.14 (m, 1H), 6.81 (d, J=8.8 Hz, 1H), 7.21 (d,J=8.8 Hz, 1H).

(3) 4-Allyl-5-methoxy-2-methylbenzoxazole

1.44 g of 4-allyl-5-hydroxy-2-methylbenzoxazole was dissolved in 5 ml ofN,N-dimethylformamide and 5 ml of acetonitrile. Thereafter, 1.05 g ofpotassium carbonate and 0.55 ml of methyl iodide were successively addedto the reaction solution. Approximately 16 hours later, water and ethylacetate were added to the reaction solution, so as to separate anorganic layer. The obtained organic layer was washed with a saturatedsodium chloride solution and then dried over anhydrous magnesiumsulfate. After removing the drying agent by filtration, the organiclayer was concentrated under a reduced pressure, and the residue wasthen purified by silica gel column chromatography (hexane/ethylacetate), so as to obtain 1.26 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.61 (s, 3H), 3.69-3.73 (m, 2H), 3.86 (s, 3H),4.96-5.05 (m, 2H), 6.02-6.14 (m, 1H), 6.86 (d, J=8.8 Hz, 1H), 7.24 (d,J=8.8 Hz, 1H).

(4)1-{1-[2-(5-methoxy-2-methylbenzoxazol-4-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was obtained from the above described4-allyl-5-methoxy-2-methylbenzoxazole according to the method describedin Example 1, (4).

¹H-NMR (CDCl₃) δ (ppm): 2.05-2.20 (m, 4H), 2.28-2.40 (m, 2H), 2.62 (s,3H), 2.68-2.80 (m, 2H), 3.16-3.33 (m, 4H), 3.88 (s, 3H), 4.32-4.45 (m,1H), 6.56 (d, J=3.2 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 7.22-7.44 (m, 3H),7.63 (d, J=8.8 Hz, 1H), 8.09.(s, 1H).

EXAMPLE 8 Synthesis of1-{1-[2-(5-methoxy-2-methylbenzoxazol-6-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) 2-Amino-4-methoxyphenol

10 g of 4-methoxy-2-nitrophenol was dissolved in 120 ml of methanol and80 ml of ethyl acetate. Thereafter, 800 mg of 10% palladium carbon wasadded to the reaction solution, followed by reduction under hydrogenatmosphere. After completion of the reaction, the catalyst was removedby filtration, and the residue was then concentration under a reducedpressure. The generated solid was suspended in hexane-t-butylmethylether, and the suspension was then filtered, so as to obtain 7.77 g ofthe subject compound.

¹H-NMR (CDCl₃) δ (ppm): 3.72 (brs, 5H), 4.33 (brs, 1H), 6.12-6.24 (m,1H), 6.33 (brs, 1H), 6.58-6.70 (m, 1H).

(2) 2-acetamide-4-methoxyphenyl acetate

2.50 g of 2-amino-4-methoxyphenol and 12.5 ml of triethylamine weredissolved in 50 ml of tetrahydrofuran. The reaction solution was cooledon ice, and then, 3.84 ml of acetyl chloride was added dropwise thereto.Thereafter, the reaction solution was stirred at room temperature. Aftercompletion of the reaction, a saturated sodium bicarbonate solution andethyl acetate were added to the reaction solution, so as to separate anorganic layer. The obtained organic layer was washed with a saturatedsodium chloride solution and then dried over anhydrous magnesiumsulfate. After removing the drying agent by filtration, the organiclayer was concentrated under a reduced pressure. The residue wassolidified from t-butylmethyl ether-ethyl acetate, so as to obtain 2.30g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.18 (s, 3H), 2.35 (s, 3H), 3.80 (s, 3H), 6.64(dd, J=2.4 Hz, 8.8 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 7.08-7.16 (brs, 1H),7.84 (d, J=2.4 Hz, 1H).

(3) 2-acetamide-5-bromo-4-methoxyphenyl acetate

2.30-g of 2-acetamide-4-methoxyphenyl acetate was dissolved in 20 ml ofN,N-dimethylformamide. The reaction solution was cooled on ice, andthen, 1.83 g of N-bromosuccinimide dissolved in 10 ml ofN,N-dimethylformamide was added thereto. Thereafter, the temperature ofthe reaction solution was increased to a room temperature, and it wasthen stirred for 12 hours. Thereafter, a saturated sodium chloridesolution and ethyl acetate were added to the reaction solution, so as toseparate an organic layer. The obtained organic layer was washed with asaturated sodium chloride solution and then dried over anhydrousmagnesium sulfate. After removing the drying agent by filtration, theorganic layer was concentrated under a reduced pressure. The residue wascrystallized from hexane-ethyl acetate, so as to obtain 2.70 g of thesubject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.19 (s, 3H), 2.36 (s, 3H), 3.89 (s, 3H), 7.14(brs, 1H), 7.32 (s, 1H), 7.99 (s, 1H).

(4) 6-bromo-5-methoxy-2-methylbenzoxazole

2.70 g of 2-acetamide-5-bromo-4-methoxyphenyl acetate was dissolved in60 ml of methanol and 40 ml of tetrahydrofuran. Thereafter, 6.18 g ofpotassium carbonate was added to the reaction solution, and the obtainedmixture was then stirred at room temperature. After completion of thereaction, the reaction solution was adjusted to be pH 2 to 3 withaddition of 5 N hydrochloric acid. Thereafter, ethyl acetate was addedto the reaction solution, so as to separate an organic layer. Theobtained organic layer was washed with a saturated sodium chloridesolution and then dried over anhydrous magnesium sulfate. After removingthe drying agent by filtration, the organic layer was concentrated undera reduced pressure, so as to obtain 2.14 g of crude4′-bromo-2′-hydroxy-5′-methoxyacetanilide. 2.14 g of the thus obtainedcrude 4′-bromo-2′-hydroxy-5′-methoxyacetanilide was dissolved in 40 mlof acetic acid, and the reaction solution was then stirred while heatingat 140° C. Approximately 20 hours later, the reaction solution was stoodto cool, and then concentrated under a reduced pressure. Thereafter, asaturated sodium bicarbonate aqueous solution and ethyl acetate wereadded to the reaction solution, so as to separate an organic layer. Theobtained organic layer was washed with a saturated sodium chloridesolution and then dried over anhydrous magnesium sulfate. After removingthe drying agent by filtration, the organic layer was concentrated undera reduced pressure. The residue was suspended in methanol-t-butyl methylether, and the suspension was then filtered, so as to obtain 787 mg ofthe subject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.61 (s, 3H), 3.93 (s, 3H), 7.16 (s, 1H), 7.67(s, 1H)

(5) 6-allyl-5-methoxy-2-methylbenzoxazole

400 mg of 6-bromo-5-methoxy-2-methylbenzoxazole was dissolved in 5 ml oftoluene. Thereafter, 769 μl of allyl tributyl tin and 57 mg oftetrakis(triphenylphosphine)palladium were successively added to thereaction solution. Thereafter, the reaction solution was heated toreflux under nitrogen atmosphere. Approximately 14 hours later, thereaction solution was stood to cool and then filtered through celite,followed by concentration under a reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate), soas to obtain 202 mg of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.59 (s, 3H), 3.45 (d, J=6.4 Hz, 2H), 3.86 (s,3H), 5.02-5.10 (m, 2H), 5.94-6.06 (m, 1H), 7.08 (s, 1H), 7.23 (s, 1H).

(6)1-{1-[2-(5-methoxy-2-methylbenzoxazol-6-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was obtained from the above described6-allyl-5-methoxy-2-methylbenzoxazole according to the method describedin Example 1, (4).

¹H-NMR (CDCl₃) δ (ppm): 2.06-2.16 (m, 4H), 2.24-2.36 (m, 2H), 2.61 (s,3H), 2.63-2.71 (m, 2H), 2.90-2.98 (m, 2H), 3.17-3.26 (m, 2H), 3.88 (s,3H), 4.34-4.46 (m, 1H), 6.57 (dd, J=0.8 Hz, 3.2 Hz, 1H), 7.10 (s, 1H),7.28 (s, 1H), 7.37-7.42 (m, 2H), 7.63 (dd, J=0.8 Hz, 8.4 Hz, 1H), 8.10(s, 1H).

EXAMPLE 9 Synthesis of1-{1-[2-(8-methoxy-4-methyl-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) Methyl 2-hydroxy-4-methoxy-5-(3-methyl-2-butenyl)benzoate

The subject compound was obtained from methyl2-hydroxy-4-methoxybenzoate according to the methods described inExample 4, (1)-(2).

¹H-NMR (CDCl₃) δ (ppm): 1.70 (s, 3H), 1.74 (d, J=1.2 Hz, 3H), 3.20 (dd,J=0.8, 7.2 Hz, 2H), 3.84 (s, 3H), 3.90 (s, 3H), 5.20-5.28 (m, 1H), 6.41(s, 1H), 7.51 (t, J=0.8 Hz, 1H), 10.9 (s, H).

(2)8-Methoxy-7-(3-methyl-2-butenyl)-3,4-dihydro-2H-benz[f][1,4]oxazepin-5-one

2.00 g of methyl 2-hydroxy-4-methoxy-5-(3-methyl-2-butenyl)benzoate,1.29 g of N-(t-butoxycarbonyl)-2-aminoethanol, and 2.31 g oftriphephenylphosphine were dissolved in 50 ml of tetrahydrofuran. Theobtained mixture was cooled on ice. Thereafter, 1.73 ml ofdiisopropylazodicarboxylate was added to the reaction solution at thesame temperature, and the temperature was then raised to a roomtemperature. After completion of the reaction, the reaction solution wasconcentrated. The residue was purified by NH silica gel columnchromatography (hexane/ethyl acetate), so as to obtain 1.54 g of methyl2-(2-t-butoxycarbonylaminoethoxy)-4-methoxy-5-(3-methyl-2-butenyl)benzoate.The obtained product was dissolved in 15 ml of methanol, and theobtained mixture was cooled on ice. Thereafter, 10 ml of a 4 Nhydrochloric acid-ethyl acetate solution was added to the reactionsolution. After completion of the reaction, the reaction solution wasconcentrated under a reduced pressure. Ethyl acetate was added to theresidue, and the obtained mixture was adjusted to be approximately pH 11with addition of a 5 N sodium hydroxide aqueous solution and a saturatedsodium bicarbonate aqueous solution. The organic layer was dried overanhydrous magnesium sulfate. After removing the drying agent byfiltration, the organic layer was concentrated under a reduced pressure.1.06 g of the obtained residue was dissolved in 20 ml of toluene, andthe obtained solution was heated to reflux. After completion of thereaction, the reaction solution was concentrated. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate), soas to obtain 601 mg of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.70 (s, 3H), 1.72 (d, J=1.2 Hz, 3H), 3.26 (d,J=7.2 Hz, 2H), 3.48-3.55 (m, 2H), 3.84 (s, 3H), 4.35-4.41 (m, 2H),5.25-5.32 (m, 1H), 6.44 (s, 1H), 6.47 (brs, 1H), 7.80 (s, 1H).

(3)8-Methoxy-4-methyl-7-(3-methyl-2-butenyl)-3,4-dihydro-2H-benz[f][1,4]oxazepin-5-one

601 mg of8-methoxy-7-(3-methyl-2-butenyl)-3,4-dihydro-2H-benz[f][1,4]oxazepin-5-onewas dissolved in 15 ml of N,N-dimethylformamide. Thereafter, 120 mg ofsodium hydride was added to the reaction solution. Ten minutes later,215 μl of methyl iodide was added to the reaction solution, and theobtained mixture was then stirred at room temperature. After completionof the reaction, a saturated ammonium chloride aqueous solution andethyl acetate were added to the reaction solution, so as to separate anorganic layer. The organic layer was washed with a saturated sodiumchloride aqueous solution and then dried over anhydrous magnesiumsulfate. After removing the drying agent by filtration, the organiclayer was concentrated under a reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate), soas to obtain 513 mg of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.69 (s, 3H), 1.72 (d, J=1.2 Hz, 3H), 3.19 (s,3H), 3.26 (d, J=7.6 Hz, 2H), 3.50-3.60 (m, 2H), 3.82 (s, 3H), 4.32-4.43(m, 2H), 5.24-5.33 (m, 1H), 6.43 (s, 1H), 7.63 (s, 1H).

(4)1-{1-[2-(8-Methoxy-4-methyl-5-oxo-2,-3,4,5-tetrahydrobenz[f][1,4]oxazepin-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was obtained from8-methoxy-4-methyl-7-(3-methyl-2-butenyl)-3,4-dihydro-2H-benz[f][1,4]oxazepin-5-oneaccording to the method described in Example 4, (4).

¹H-NMR (CDCl₃) δ (ppm): 2.06-2.35 (m, 6H), 2.60-2.70 (m, 2H), 2.78-2.88(m, 2H), 3.15-3.26 (m, 2H), 3.20 (s, 3H), 3.53-3.58 (m, 2H), 3.83 (s,3H), 4.32-4.44 (m, 3H), 6.44 (s, 1H), 6.56 (dd, J=0.4 Hz, 3.2 Hz, 1H),7.36-7.46 (m, 2H), 7.63 (dd, J=0.4 Hz, 8.0 Hz, 1H), 7.69 (s, 1H), 8.09(s, 1H).

EXAMPLE 10 Synthesis of1-{1-[2-(8-methoxy-4-methyl-5-oxo-2,3,4,5-tetrahydrobenz[f][1,4]oxazepin-7-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide

The subject compound was synthesized fromN-methyl-1-(piperidin-4-yl)-1H-indole-6-carboxamide according to themethod described in Example 9.

¹H-NMR (CDCl₃) δ (ppm): 2.03-2.37 (m, 6H), 2.55-2.74 (m, 2H), 2.76-2.90(m, 2H), 3.06 (d, J=4.80 Hz, 3H), 3.12-3.26 (m, 2H), 3.20 (s, 3H),3.50-3.60 (m, 2H), 3.84 (s, 3H), 4.30-4.43 (m, 3H), 6.28 (brs, 1H), 6.44(s, 1H), 6.54 (d, J=3.2 Hz, 1H), 7.30-7.42 (m, 2H), 7.61 (d, J=8.0 Hz,1H), 7.69 (s, 1H), 8.03 (brs, 1H).

EXAMPLE 11 Synthesis of1-{1-[2-(5,7-dimethoxy-1-methoxyiminoindan-4-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) 4-Bromo-5,7-dimethoxyindan-1-one O-methyloxime

845 mg of 5,7-dimethoxyindan-1-one was dissolved in 40 ml ofdichloromethane. Thereafter, 822 mg of N-bromosuccinimide was added tothe reaction solution. After completion of the reaction, chloroform wasadded to the-reaction solution. The organic layer was washed with asaturated sodium chloride solution and then dried over anhydrousmagnesium sulfate. After removing the drying agent by filtration, theorganic layer was concentrated under a reduced pressure. The residue wassuspended in acetone, and the suspension was filtered, so as to obtain1.03 g of 4-bromo-5,7-dimethoxyindan-1-one. The obtained product wassuspended in a mixed solution consisting of 30 ml of methanol, 10 ml oftetrahydrofuran, and 20 ml of chloroform. Thereafter, 952 mg ofmethoxylamine hydrochloride and 935 mg of sodium acetate were added tothe reaction solution, and the obtained mixture was stirred at roomtemperature. Approximately 4 hours later, 952 mg of methoxylaminehydrochloride and 935 mg of sodium acetate were further added to thereaction solution. After completion of the reaction, the reactionsolution was concentrated. A saturated sodium bicarbonate aqueoussolution and ethyl acetate were added to the resultant product, so as toseparate an organic layer. The organic layer was washed with a saturatedsodium bicarbonate aqueous solution and a saturated sodium chloridesolution, and then dried over anhydrous magnesium sulfate. Afterremoving the drying agent by filtration, the organic layer wasconcentrated under a reduced pressure. The residue was suspended int-butyl methyl ether, and the suspension was filtered, so as to obtain896 mg of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.90-3.00 (m, 4H), 3.95 (s, 3H), 3.96 (s, 3H),4.00 (s, 3H), 6.38 (s, 1H).

(2)1-{1-[2-(5,7-Dimethoxy-1-methoxyiminoindan-4-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was obtained from 4-bromo-5,7-dimethoxyindan-1-oneO-methyloxime according to the methods described in Example 8, (5)-(6).

¹H-NMR (CDCl₃) δ (ppm): 2.13 (brs, 4H), 2.21-2.36 (m, 2H), 2.46-2.58 (m,2H), 2.72-2.84 (m, 2H), 2.96 (brs, 4H), 3.16-3.29 (m, 2H), 3.89 (s, 3H),3.96 (s, 3H), 4.01 (s, 3H), 4.34-4.46 (m, 1H), 6.37 (s, 1H), 6.58 (d,J=2.4 Hz, 1H), 7.36-7.46 (m, 2H), 7.65 (d, J=8.4 Hz, 1H), 8.12 (brs,1H).

EXAMPLE 12 Synthesis of1-{1-[2-(8-methoxy-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) Methyl2-(3-ethoxycarbonylpropoxy)-4-methoxy-5-(3-methyl-2-butenyl)benzoate

3.00 g of methyl 2-hydroxy-4-methoxy-5-(3-methyl-2-butenyl)benzoate wasdissolved in 30 ml of N,N-dimethylformamide. Thereafter, 2.16 g ofpotassium carbonate and 2.23 ml of ethyl 4-bromobutylate were added tothe reaction solution, and the obtained mixture was then stirred whileheating at 80° C. 829 mg of potassium carbonate and 0.86 ml of ethyl4-bromobutylate were added thereto at the midpoint of the reaction.After completion of the reaction, ethyl acetate was added to thereaction solution. The obtained organic layer was washed with asaturated ammonium chloride aqueous solution and a saturated sodiumchloride solution, and then dried over anhydrous magnesium sulfate.After removing the drying agent by filtration, the organic layer wasconcentrated under a reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate), so as to obtain2.88 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.25 (t, J=7.2 Hz, 3H), 1.70 (s, 3H), 1.73 (d,J=1.2 Hz, 3H), 2.10-2.20 (m, 2H), 2.61 (t, J=7.2 Hz, 2H), 3.23 (d, J=7.2Hz, 2H), 3.85 (s, 3H), 3.87 (s, 3H), 4.09 (t, J=6.0 Hz, 2H), 4.13 (q,J=7.2 Hz, 2H), 5.20-5.30 (m, 1H), 6.43 (s, 1H), 7.64 (s, 1H).

(2) 8-Methoxy-7-(3-methyl-2-butenyl)-3,4-dihydro-2H-benz[b]oxepin-5-one

80 ml of a tetrahydrofuran solution containing 18.6 mmol lithiumbis(trimethylsilyl)amide was cooled to −75° C. 3.23 g of methyl2-(3-ethoxycarbonylpropoxy)-4-methoxy-5-(3-methyl-2-butenyl)benzoate wasdissolved in 8 ml of tetrahydrofuran, and the obtained solution wasadded dropwise to the above solution. After completion of the dropping,the reaction solution was warmed to 0° C. After completion of thereaction, a saturated ammonium chloride aqueous solution and ethylacetate were added to the reaction solution, so as to separate anorganic layer. The obtained organic layer was washed with a saturatedsodium chloride aqueous solution and then dried over anhydrous magnesiumsulfate. After removing the drying agent by filtration, the organiclayer was concentrated under a reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate), soas to obtain 969 mg of ethyl8-methoxy-7-(3-methyl-2-butenyl)-5-oxo-2,3,4,5-tetrahydrobenz[b]oxepin-4-carboxylate.Thereafter, 751 mg of the obtained compound was dissolved in 15 ml oftetrahydrofuran. While the reaction solution was stirred under heatingat 70° C., 4 ml of a 5 N sodium hydroxide aqueous solution was addedthereto in 3 batches. Approximately 2 hours later, tetrahydrofuran as areaction solution was concentrated under a reduced pressure, and 10 mlof ethanol was then added thereto. Thereafter, 5 ml of 5 N hydrochloricacid was added to this ethanol solution, and the mixture was heated toreflux again. After completion of the reaction, ethyl acetate was addedto the reaction solution, and the obtained organic layer was washed witha saturated sodium chloride aqueous solution. The organic layer was thendried over anhydrous magnesium sulfate. After removing the drying agentby filtration, the organic layer was concentrated under a reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate), so as to obtain 422 mg of the subject compound.

¹H-NMR (CDCl₃): δ 1.69 (d, J=0.4 Hz, 3H), 1.72 (d, J=1.2 Hz, 3H), 2.18(quintet, J=6.8 Hz, 2H), 2.85 (t, J=6.8 Hz, 2H), 3.24 (d, J=6.8 Hz, 2H),3.85 (s, 3H), 4.22 (t, J=6.8 Hz, 2H), 5.22-5.30 (m, 1H), 6.51 (s, 1H),7.58 (s, 1H).

(3)1-{1-[2-(8-methoxy-5-oxo-2,3,4,5-tetrahydrobenz[b]oxepin-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was obtained from8-methoxy-7-(3-methyl-2-butenyl)-3,4-dihydro-2H-benz[b]oxepin-5-oneaccording to the method described in Example 4, (4).

¹H-NMR (CDCl₃) δ (ppm): 2.12 (brs, 4H), 2.20 (quintet, J=6.8 Hz, 2H),2.29 (brs, 2H), 2.63 (brs, 2H), 2.74-2.93 (m, 2H), 2.88 (t, J=6.8 Hz,2H), 3.10-3.30 (m, 2H), 3.87 (s, 3H), 4.24 (t, J=6.8 Hz, 2H), 4.32-4.46(m, 1H), 6.54 (s, 1H), 6.57 (dd, J=0.8, 3.2 Hz, 1H), 7.36-7.48 (m, 2H),7.62-7.68 (m, 2H), 8.11 (brs, 1H).

EXAMPLE 13 Synthesis of1-{1-[2-(8-methoxy-5-methoxyimino-2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

97 mg of1-(1-(2-(8-methoxy-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl)ethyl)piperidin-4-yl)-1H-indole-6-carboxamidewas dissolved in a mixed solution consisting of 4 ml of methanol, 2 mlof tetrahydrofuran, and 2 ml of chloroform. Thereafter, 105 mg ofmethoxylamine hydrochloride and 103 mg of sodium acetate were added tothe reaction solution, and the obtained mixture was then stirred at roomtemperature. At the midpoint of the reaction, 1 g of methoxylaminehydrochloride and 1 g of sodium acetate were further added thereto.After completion of the reaction, a 1 N sodium hydroxide aqueoussolution, a saturated sodium bicarbonate aqueous solution, andchloroform were added to the reaction solution, so as to separate anorganic layer. The obtained organic layer was washed with a saturatedsodium bicarbonate aqueous solution and a saturated sodium chloridesolution, and then dried over anhydrous magnesium sulfate. Afterremoving the drying agent by filtration, the organic layer wasconcentrated under a reduced pressure. The residue was solidified fromt-butyl methyl ether-ethyl acetate, so as to obtain 70 mg of the subjectcompound.

¹H-NMR (CDCl₃) δ (ppm): 1.95-2.05 (m, 2H), 2.05-2.40 (m, 6H), 2.55-2.73(m, 2H), 2.75-2.90 (m, 2H), 2.86 (t, J=6.8 Hz, 2H), 3.15-3.30 (m, 2H),3.82 (s, 3H), 3.98 (s, 3H), 4.17 (t, J=6.0 Hz, 2H), 4.32-4.46 (m, 1H),6.50 (s, 1H), 6.57 (d, J=3.2 Hz, 1H), 7.35 (s, 1H), 7.38-7.46 (m, 2H),7.65 (d, J=8.4 Hz, 1H), 8.11 (brs, 1H)

EXAMPLE 14 Synthesis of1-{1-[2-(5-methoxy-2,2-dimethyl-1-oxoindan-4-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) 5-hydroxy-2,2-dimethylindanone

7.78 g of potassium t-butoxide was dissolved in 66.3 ml of t-butanol and150 ml of toluene. Thereafter, 5.00 g of 5-methoxyindanone dissolved in170 ml of toluene was added dropwise to the reaction solution at roomtemperature. Approximately 10 minutes later, 4.79 ml of methyl iodidewas added to the reaction solution. After completion of the reaction, asaturated ammonium chloride aqueous solution and ethyl acetate wereadded to the reaction solution, so as to separate an organic layer. Theorganic layer was then dried over anhydrous magnesium sulfate. After theorganic layer had been filtered through celite, the drying agent wasremoved by filtration. Thereafter, the organic layer was concentratedunder a reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate), so as to obtain 2.08 g of5-methoxy-2,2-dimethylindanone. The obtained product was dissolved in 9ml of methanesulfonic acid. Then, 2.45 g of methionine was added to thereaction solution, and the obtained mixture was heated to 110° C. Aftercompletion of the reaction, a saturated sodium chloride aqueous solutionand ethyl acetate were added to the reaction solution, so as to separatean organic layer. The organic layer was then dried over anhydrousmagnesium sulfate. After removing the drying agent by filtration, theorganic layer was concentrated under a reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate), soas to obtain 1.41 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.24 (s, 6H), 2.94 (s, 2H), 6.79-6.90 (m, 3H),7.68 (dd, J=0.4, 8.0 Hz, 1H).

(2)1-{1-[2-(5-methoxy-2,2-dimethyl-1-oxoindan-4-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was obtained from 5-hydroxy-2,2,-dimethylindanoneaccording to the methods described in Example 7, (1)-(4).

¹H-NMR (CDCl₃) δ (ppm): 1.25 (s, 6H), 2.00-2.23 (m, 4H), 2.25-2.40 (m,2H), 2.50-2.66 (m, 2H), 2.80-3.00 (m, 2H), 2.95 (s, 2H), 3.15-3.33 (m,2H), 3.94 (s, 3H), 4.33-4.48 (m, 1H), 6.58 (d, J=3.2 Hz, 1H), 6.94 (d,J=8.4 Hz, 1H), 7.36-7.46 (m, 2H), 7.65 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.8Hz, 1H), 8.12 (s, 1H).

EXAMPLE 15 Synthesis of1-{1-[2-(6-methoxy-2-methylbenzoxazol-7-yl)ethyl]piperidin-4-yl})-N-methyl-1H-indole-6-carboxamide

The subject compound was synthesized usingN-methyl-1-(piperidin-4-yl)-1H-indole-6-carboxamide according to themethod described in Example 3, (5).

¹H-NMR (CDCl₃) δ (ppm): 2.13 (brs, 4H), 2.33 (brs, 2H), 2.62 (s, 3H),2.72 (brs, 2H), 3.07 (d, J=4.8 Hz, 3H), 3.02-3.18 (m, 2H), 3.20-3.34 (m,2H), 3.90 (s, 3H), 4.34-4.48 (m, 1H), 6.24 (brs, 1H), 6.56 (d, J=2.8 Hz,1H), 6.89 (d, J=8.4 Hz, 1H), 7.32-7.48 (m, 3H), 7.63 (d, J=8.0 Hz, 1H),8.04 (brs, 1H).

EXAMPLE 16 Synthesis of1-{1-[2-(6-methoxy-2-methylbenzoxazol-5-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide

The subject compound was synthesized usingN-methyl-1-(piperidin-4-yl)-1H-indole-6-carboxamide according to themethod described in Example 4, (4).

¹H-NMR (CDCl₃) δ (ppm): 2.12 (brs, 4H), 2.30 (brs, 2H), 2.60 (s, 3H),2.62-2.74 (m, 2H), 2.94 (brs, 2H), 3.06 (d, J=5.2 Hz, 3H), 3.12-3.30 (m,2H), 3.89 (s, 3H), 4.32-4.45 (m, 1H), 6.24 (brs, 1H), 6.55 (d, J=3.2 Hz,1H), 6.99 (s, 1H), 7.32-7.42 (m, 2H), 7.43 (s, 1H), 7.62 (d, J=8.4 Hz,1H), 8.05 (brs, 1H)

EXAMPLE 17 Synthesis of1-{1-[2-(6-methoxy-3-methylbenz[d]isoxazol-7-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide

65 mg of1-(1-(2-(6-methoxy-3-methylbenz[d]isoxazol-7-yl)ethyl)piperidin-4-yl)-1H-indole-6-carboxamideobtained in Example 1 was dissolved in 1 ml of N,N-dimethylformamide,and then, 7.2-mg of 60% sodium hydride was added thereto. The reactionsolution was stirred at room temperature for 5 minutes, and 11.2 μl ofmethyl iodide was then added to the reaction solution. After completionof the reaction, water and ethyl acetate were added to the reactionsolution, so as to separate an organic layer. The obtained organic layerwas washed with a saturated sodium bicarbonate aqueous solution and thendried over anhydrous magnesium sulfate. After removing the drying agentby filtration, the organic layer was concentrated under a reducedpressure. The residue was purified by NH silica gel columnchromatography (hexane/ethyl acetate), so as to obtain 17 mg of thesubject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.11 (brs, 4H), 2.26-2.42 (m, 2H), 2.54 (s, 3H),2.68-2.82 (m, 2H), 3.06 (d, J=5.2 Hz, 3H), 3.10-3.20 (m, 2H), 3.22-3.32(m, 2H), 3.95 (s, 3H), 4.32-4.43 (m, 1H), 6.30 (brs, 1H), 6.55 (d, J=3.2Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 7.34-7.42 (m, 2H), 7.43 (d, J=8.4 Hz,1H), 7.62 (d, J=8.4 Hz, 1H), 8.04 (s, 1H).

EXAMPLE 18 Synthesis of1-{1-[2-(6-methoxy-3-methylbenz[d]isoxazol-5-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide

The subject compound was synthesized using1-(1-(2-(6-methoxy-3-methylbenzo[d]isoxazol-5-yl)ethyl)piperidin-4-yl)-1H-indole-6-carboxamideobtained in Example 2 according to the method described in Example 17.

¹H-NMR (CDCl₃) δ (ppm): 2.13 (brs, 4H), 2.21-2.39 (m, 2H), 2.54 (s, 3H),2.60-2.73 (m, 2H), 2.88-3.00 (m, 2H), 3.06 (d, J=5.2 Hz, 3H), 3.15-3.30(m, 2H), 3.93 (s, 3H), 4.32-4.46 (m, 1H), 6.28 (brs, 1H), 6.56 (d, J=2.8Hz, 1H), 6.97 (s, 1H), 7.32-7.40 (m, 3H), 7.62 (d, J=8.0 Hz, 1H), 8.08(s, 1H).

EXAMPLE 19 Synthesis of1-{1-[2-(2-methoxy-5-methoxyimino-5,6,7,8-tetrahydronaphthalen-1-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

200 mg of 5-(2,3-dihydroxypropyl)-6-methoxy-1-tetralone synthesized from6-hydroxy-1-tetralone according to the methods described in Example 7,(1)-(4), was dissolved in a mixed solution consisting of 5 ml ofmethanol and 3 ml of tetrahydrofuran. Thereafter, 401 mg ofmethoxylamine hydrochloride and 394 mg of sodium acetate were added tothe reaction solution, and the obtained mixture was then stirred at roomtemperature. After completion of the reaction, a saturated sodiumbicarbonate aqueous solution and ethyl acetate were added to thereaction solution, so as to separate an organic layer. The obtainedorganic layer was washed with a saturated sodium bicarbonate aqueoussolution and a saturated sodium chloride solution, and then dried overanhydrous magnesium sulfate. After removing the drying agent byfiltration, the organic layer was concentrated under a reduced pressure,so as to obtain 183 mg of5-(2,3-dihydroxypropyl)-6-methoxy-3,4-dihydro-2H-naphthalen-1-oneO-methyloxime. The subject compound was obtained from the thus obtainedcompound according to the method described in Example 1, (4).

¹H-NMR (CDCl₃) δ (ppm): 1.80-1.90 (m, 2H), 2.15 (brs, 4H), 2.32 (brs,2H), 2.51 (brs, 2H), 2.65-2.80 (m, 4H), 2.85-3.02 (m, 2H), 3.15-3.35 (m,2H), 3.86 (s, 3H), 3.97 (s, 3H), 4.34-4.48 (m, 1H), 6.58 (d, J=3.2 Hz,1H), 6.77 (d, J=8.8 Hz, 1H), 7.38-7.46 (m, 2H), 7.65 (d, J=8.0 Hz, 1H),7.90 (d, J=8.8 Hz, 1H), 8.12 (s, 1H).

EXAMPLE 20 Synthesis of1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide

126 mg of 8-allyl-7-methoxy-2,2-dimethyl-4-oxochroman was dissolved in12 ml of t-butanol-water (1:1) under nitrogen atmosphere. Thereafter,0.72 g of AD-mix-β was added to the reaction solution, and the obtainedmixture was then stirred at room temperature for 24 hours. Thereafter,0.77 g of sodium sulfite was added to the reaction solution whilecooling on ice, and the obtained mixture was stirred at room temperaturefor 1 hour. The reaction solution was diluted with ethyl acetate, andthen washed with a saturated sodium chloride aqueous solution. Theorganic layer was dried over magnesium sulfate and then filtered. Theorganic layer was then concentrated under a reduced pressure, so as toobtain 145 mg of8-(2,3-dihydroxypropyl)-7-methoxy-2,2-dimethyl-4-oxochroman. Thiscompound was used in the following reaction without-furtherpurification.

145 mg of 8-(2,3-dihydroxypropyl)-7-methoxy-2,2-dimethyl-4-oxochromanwas dissolved in 3 ml of tetrahydrofuran and 4 ml of methanol.Thereafter, 7 ml of water containing 0.22 g of sodium metaperiodate wasadded to the reaction solution while cooling on ice, and the obtainedmixture was then stirred at room temperature for 30 minutes. Thereaction solution was diluted with ethyl acetate, and then washed with asaturated sodium chloride aqueous solution. The organic layer was driedover magnesium sulfate and then filtered. The organic layer was thenconcentrated under a reduced pressure, so as to obtain 120 mg of(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)acetaldehyde. This compoundwas used in the following reaction without further purification.

120 mg of N-methyl-1-(piperidin-4-yl)-1H-indole-6-carboxamide and 120 mgof (7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)acetaldehyde were dissolvedin 8 ml of methylene chloride. Thereafter, 0.05 ml of acetic acid and0.15 g of sodium triacetoxyborohydride were added to the reactionsolution, and the obtained mixture was then stirred at room temperaturefor 1 hour. Thereafter, a saturated sodium bicarbonate aqueous solutionwas added to the reaction solution, followed by extraction withmethylene chloride. The extract was dried over magnesium sulfate andthen filtered. The filtrate was then concentrated under a reducedpressure. The residue was purified by silica gel column chromatography(methanol-ethyl acetate), so as to obtain 210 mg of the subjectcompound.

¹H-NMR (DMSO-d₆) δ (ppm): 1.40 (s, 6H), 1.92-2.10 (m, 4H), 2.22-2.33 (m,2H), 2.40-2.50 (m, 2H), 2.72 (s, 2H), 2.74-2.83 (m, 2H), 2.82 (d, J=4.4Hz, 3H), 3.08-3.17 (m, 2H), 3.87 (s, 3H), 4.35-4.47 (m, 1H), 6.50 (d,J=3.2 Hz, 1H), .6.75 (d, J=9.2 Hz, 1H), 7.51-7.59 (m, 2H), 7.62-7.69 (m,2H), 8.06 (s, 1H), 8.29-8.37 (m, 1H).

EXAMPLE 22 Synthesis of1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) 7-Allyloxy-2,2-dimethyl-4-oxochroman

9.74 g of 7-hydroxy-2,2-dimethyl-4-oxochroman (CAS#: 17771-33-4) wasdissolved in 150 ml of N,N-dimethylformamide. Thereafter, 10.5 g ofpotassium carbonate and 7.36 g of allyl bromide were added to thereaction solution, and the obtained mixture was stirred at roomtemperature overnight. Thereafter, the reaction solution was dilutedwith ethyl acetate, and then washed with water and a saturated sodiumchloride aqueous solution. The organic layer was dried over magnesiumsulfate and then concentrated under a reduced pressure. The residue wasthen purified by silica gel column chromatography (hexane-ethylacetate), so as to obtain 11.0 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.45 (s, 6H), 2.67 (s, 2H), 4.53-4.58 (m, 2H),5.28-5.35 (m, 1H), 5.37-5.46 (m, 1H), 5.98-6.09 (m, 1H), 6.38 (d, J=2.4Hz, 1H), 6.56 (dd, J=2.4, 8.8 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H).

(2) 8-Allyl-7-hydroxy-2,2-dimethyl-4-oxochroman (a) and6-allyl-7-hydroxy-2,2-dimethyl-4-oxochroman (b)

1.97 g of 7-allyloxy-2,2-dimethyl-4-oxochroman was dissolved in 5 ml ofN,N-dimethylaniline under nitrogen atmosphere, and the reaction solutionwas heated to reflux for 6 hours. Thereafter, the reaction solution wascooled to room temperature. It was then purified by silica gel columnchromatography (hexane-ethyl acetate), so as to obtain a mixtureconsisting of the subject compounds (a) and (b). The mixture was furtherpurified by high performance liquid chromatography (ODS-AM;acetonitrile-water), so as to obtain 1.05 g of the subject compound (a)and 95 mg of the subject compound (b).

Isomer (a)

¹H-NMR (CDCl₃) δ (ppm): 1.44 (s, 6H), 2.66 (s, 2H), 3.40-3.46 (m, 2H),5.03-5.17 (m, 2H), 5.55 (s, 1H), 5.86-6.00 (m, 1H), 6.47 (d, J=8.8 Hz,1H), 7.71 (d, J=8.8 Hz, 1H).

Isomer (b)

¹H-NMR (CDCl₃) δ (ppm): 1.44 (s, 6H), 2.65 (s, 2H), 3.34-3.37 (m, 2H),5.14-5.21 (m, 2H), 5.60 (s, 1H), 5.93-6.04 (m, 1H), 6.32 (s, 1H), 7.63(s, 1H).

(3) 8-Allyl-7-methoxy-2,2-dimethyl-4-oxochroman

567 mg of 8-allyl-7-hydroxy-2,2-dimethyl-4-oxochroman was dissolved in15 ml of N,N-dimethylformamide. Thereafter, 0.51 g of potassiumcarbonate and 0.42 g of iodomethane were added to the reaction solution,and the obtained mixture was then stirred at room temperature overnight.The reaction solution was diluted with ethyl acetate, and then washedwith a saturated ammonium chloride aqueous solution and a saturatedsodium chloride aqueous solution. The organic layer was dried overmagnesium sulfate, and then concentrated under a reduced pressure. Theresidue was purified by silica gel column chromatography (hexane-ethylacetate), so as to obtain 582 mg of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.44 (s, 6H), 2.67 (s, 2H), 3.36-3.40 (m, 2H),3.88 (s, 3H), 4.92-5.04 (m, 2H), 5.84-5.95 (m, 1H), 6.58 (d, J=8.8 Hz,1H), 7.80 (d, J=8.8 Hz, 1H).

(4)1-(1-(2-(7-Methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl)piperidin-4-yl)-1H-indole-6-carboxamide

150 mg of 8-allyl-7-methoxy-2,2-dimethyl-4-oxochroman was dissolved in16 ml of t-butanol-water (1:1). Thereafter, 0.85 g of AD-mix-β was addedto the reaction solution, and the obtained mixture was then stirred atroom temperature overnight. Thereafter, 0.91 g of sodium sulfite wasadded to the reaction solution while cooling on ice, and the obtainedmixture was stirred at room temperature for 1 hour. The reactionsolution was diluted with ethyl acetate and then washed with a saturatedsodium chloride aqueous solution. The organic layer was dried overmagnesium sulfate and then concentrated under reduced pressure, so as toobtain 171 mg of8-(2,3-dihydroxypropyl)-7-methoxy-2,2-dimethyl-4-oxochroman. Thiscompound was used in the following reaction without furtherpurification.

171 mg of 8-(2,3-dihydroxypropyl)-7-methoxy-2,2-dimethyl-4-oxochromanwas dissolved in 4 ml of tetrahydrofuran and 4 ml of methanol.Thereafter, 8 ml of water containing 0.26 g of sodium metaperiodate wasadded to the reaction solution while cooling on ice, and the obtainedmixture was then stirred at room temperature for 30 minutes. Thereaction solution was diluted with ethyl acetate and then washed with asaturated sodium chloride aqueous solution. The organic layer was driedover magnesium sulfate and then concentrated under a reduced pressure,so as to obtain 163 mg of(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)acetaldehyde. This compoundwas used in the following reaction without further purification.

120 mg of 1-(piperidin-4-yl)-1H-indole-6-carboxamide and 163 mg of(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)acetaldehyde were dissolved in10 ml of methylene chloride. Thereafter, 0.06 ml of acetic acid wasadded to the reaction solution, and the obtained mixture was thenstirred at room temperature for 15 minutes. Thereafter, 157 mg of sodiumtriacetoxyborohydride was added to the reaction solution, and theobtained mixture was then stirred at room temperature for 1 hour.Thereafter, a saturated sodium bicarbonate aqueous solution was added tothe reaction solution, followed by extraction with chloroform. Theextract was dried over magnesium sulfate and then concentrated under areduced pressure. The residue was purified by NH silica gel columnchromatography (methanol-ethyl acetate), followed by solidification withethyl acetate, so as to obtain 220 mg of the subject compound.

¹H-NMR (DMSO-d₆) δ (ppm): 1.40 (s, 6H), 1.93-2.10 (m, 4H), 2.22-2.35 (m,2H), 2.42-2.50 (m, 2H), 2.72 (s, 2H), 2.74-2.82 (m, 2H), 3.08-3.17 (m,2H), 3.87 (s, 3H), 4.37-4.48 (m, 1H), 6.50 (d, J=3.2 Hz, 1H), 6.75 (d,J=8.8 Hz, 1H), 7.21 (br.s, 1H), 7.53-7.61 (m, 2H), 7.65 (d, J=8.8 Hz,1H), 7.67 (d; J=3.2 Hz, 1H), 7.91 (br.s, 1H), 8.13 (s, 1H).

EXAMPLE 23 Synthesis of1-{1-[2-(6-methoxy-1-methyl-2-oxo-1,4-dihydro-2H-benz[d][1,3]oxazin-7-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide

(1) 3-Methoxy-6-nitro-4-(2-propenyl)benzylalcohol

8.40 g of 3-hydroxy-4-(2-propenyl)benzylalcohol (Tetrahedron, 56 (2000),1873) was dissolved in 70 ml of acetic acid. Thereafter, 4.14 g ofconcentrated nitric acid and 0.6 ml of fuming nitric acid were added tothe reaction solution while cooling on ice, and the obtained mixture wasstirred at the same temperature for 20 minutes. Thereafter, the reactionsolution was adjusted to be pH 6 with addition of a 5 N sodium hydroxideaqueous solution, while cooling on ice. It was then extracted with ethylacetate. The extract was washed with a saturated sodium bicarbonateaqueous solution and a saturated sodium chloride aqueous solution. Theorganic layer was dried over magnesium sulfate and then concentratedunder a reduced pressure. The residue was then purified by silica gelcolumn chromatography (hexane-ethyl acetate), so as to obtain 4.68 g of3-hydroxy-6-nitro-4-(2-propenyl)benzylalcohol.

4.68 g of 3-hydroxy-6-nitro-4-(2-propenyl)benzylalcohol was dissolved in90 ml of N,N-dimethylformamide. Thereafter, 3.71 g of potassiumcarbonate and 3.81 g of iodomethane were added to the reaction solution,and the obtained mixture was stirred at room temperature overnight. Thereaction solution was extracted with ethyl acetate, and then washed withwater and a saturated sodium chloride aqueous solution. The organiclayer was dried over magnesium sulfate and then concentrated under areduced pressure. The residue was then purified by silica gel columnchromatography (hexane-ethyl acetate), so as to obtain 3.93 g of thesubject compound.

¹H-NMR (DMSO-d₆) δ (ppm): 3.38 (d, J=6.8 Hz, 2H), 3.94 (s, 3H), 4.87 (d,J=4.8 Hz, 2H), 5.05-5.13 (m, 2H), 5.62 (t, J=4.8 Hz, 1H), 5.89-6.02 (m,1H), 7.42 (s, 1H), 7.94 (s, 1H).

(2) 2-amino-5-methoxy-4-(2-propenyl)benzylalcohol

24 ml of ethanol-water (5:1) was added to 1.00 g of3-methoxy-6-nitro-4-(2-propenyl)benzylalcohol, 1.00 g of iron, and 2.00g of ammonium chloride. The reaction solution was stirred at 90° C. for1 hour. Thereafter, the reaction solution was cooled to a roomtemperature, and insoluble matters were then removed by filtration. Thefiltrate was concentrated under a reduced pressure. The residue wasdiluted with ethyl acetate and then washed with water and a saturatedsodium chloride aqueous solution. The organic layer was dried overmagnesium sulfate and then concentrated under a reduced pressure, so asto obtain 793 mg of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 3.32 (d, J=6.0 Hz, 2H), 3.76 (s, 3H), 4.64 (s,2H), 5.00-5.09 (m, 2H), 5.88-6.00 (m, 1H), 6.54 (s, 1H), 6.64 (s, 1H).

(3) 7-allyl-6-methoxy-1,4-dihydrobenz[d][1,3]oxazin-2-one

677 mg of 2-amino-5-methoxy-4-(2-propenyl)benzylalcohol was dissolved in20 ml of tetrahydrofuran under nitrogen atmosphere. Thereafter, 0.52 gof triphosgene and 1.46 ml of triethylamine were added to the reactionsolution while cooling on ice. The obtained mixture was then stirred atroom temperature for 30 minutes. Thereafter, while cooling on ice, waterand ammonia water were added to the reaction solution until foaming wasterminated. The reaction solution was disluted with ethyl acetate andthen washed with water and a saturated sodium chloride aqueous solution.The organic layer was dried over magnesium sulfate and then concentratedunder a reduced pressure. The residue was purified by silica gel columnchromatography (hexane-ethyl acetate) and then reprecipitated from ethylacetate, so as to obtain 485 mg of the subject compound.

¹H-NMR (DMSO-d₆) δ (ppm): 3.26 (d, J=6.4 Hz, 2H), 3.73 (s, 3H),4.99-5.06 (m, 2H), 5.22 (s, 2H), 5.83-5.95 (m, 1H), 6.65 (s, 1H), 6.86(s, 1H), 9.92 (br.s, 1H).

(4) 7-Allyl-6-methoxy-1-methyl-1,4-dihydrobenz[d][1,3]oxazin-2-one

210 mg of 7-allyl-6-methoxy-1,4-dihydrobenz[d][1,3]oxazin-2-one wasdissolved in 6 ml of N,N-dimethylformamide. Thereafter, 46 mg of 60%sodium hydride was added to the reaction solution while cooling on ice.The obtained mixture was then stirred at room temperature for 20minutes. Thereafter, while cooling on ice, 0.20 g of iodomethane wasadded to the reaction solution. The obtained mixture was then stirred atroom temperature for 2 hours. Thereafter, the reaction solution wasdiluted with ethyl acetate and then washed with water and a saturatedsodium chloride aqueous solution. The organic layer was dried overmagnesium sulfate and then concentrated under a reduced pressure. Theresidue was purified by silica gel column chromatography (hexane-ethylacetate), so as to obtain 207 mg of the subject compound.

¹H-NMR (DMSO-d₆) δ (ppm): 3.23 (s, 3H), 3.31-3.36 (m, 2H), 3.76 (s, 3H),4.99-5.07 (m, 2H), 5.19 (s, 2H), 5.89-6.00 (m, 1H), 6.87 (s, 1H), 6.95(s, 1H).

(5)1-{1-[2-(6-Methoxy-1-methyl-2-oxo-1,4-dihydro-2H-benz[d](1,3]oxazin-7-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide

160 mg of 7-allyl-6-methoxy-1-methyl-1,4-dihydrobenz[d][1,3]oxazin-2-onewas dissolved in 20 ml of t-butanol-water (1 : 1). Thereafter, 0.96 g ofAD-mix-β was added to the reaction solution, and the obtained mixturewas then stirred at room temperature overnight. Thereafter, 1.03 g ofsodium sulfite was added to the reaction solution while cooling on ice,and the obtained mixture was stirred at room temperature for 1 hour. Asaturated sodium chloride aqueous solution was added to the reactionsolution, followed by extraction with methylene chloride. The extractwas dried over magnesium sulfate and then concentrated under a reducedpressure, so as to obtain 280 mg of7-(2,3-dihydroxypropyl)-6-methoxy-1-methyl-1,4-dihydrobenz[d][1,3]oxazin-2-one.This compound was used in the following reaction without furtherpurification.

280 mg of7-(2,3-dihydroxypropyl)-6-methoxy-1-methyl-1,4-dihydrobenz[d][1,3]oxazin-2-onewas dissolved in 4 ml of tetrahydrofuran and 4 ml of methanol.Thereafter, 8 ml of water containing 0.29 g of sodium metaperiodate wasadded to the reaction solution while cooling on ice, and the obtainedmixture was then stirred at room temperature for 30 minutes. Thereaction solution was diluted with ethyl acetate and then washed with asaturated sodium chloride aqueous solution. The organic layer was driedover magnesium sulfate and then concentrated under a reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate), so as to obtain 167 mg of(6-methoxy-l-methyl-2-oxo-1,4-dihydro-2H-benz[d][1,3]oxazin-7-yl).acetaldehyde.

80 mg of N-methyl-l-(piperidin-4-yl)-1H-indole-6-carboxamide and 83 mgof(6-methoxy-1-methyl-2-oxo-1,4-dihydro-2H-benz[d][1,3]oxazin-7-yl)acetaldehydewere dissolved in 6 ml of methylene chloride. Thereafter, 0.04 ml ofacetic acid and 99 mg of sodium triacetoxyborohydride were added to thereaction solution, and the obtained mixture was then stirred at roomtemperature for 3 hours. Thereafter, a saturated sodium bicarbonateaqueous solution was added to the reaction solution, and then extractedwith methylene chloride. The extract was dried over magnesium sulfateand then concentrated under a reduced pressure. The residue was purifiedby silica gel column chromatography (methanol-ethyl acetate), so as toobtain 141 mg of the subject compound.

¹H-NMR (DMSO-d₆) δ (ppm): 1.92-2.10 (m, 4H), 2.23-2.32 (m, 2H),2.51-2.61 (m, 2H), 2.77-2.85 (m, 2H), 2.82 (d, J=4.4 Hz, 3H), 3.08-3.15(m, 2H), 3.26 (s, 3H), 3.79 (s, 3H), 4.37-4.47 (m, 1H), 5.19 (s, 2H),6.50 (d, J=3.2 Hz, 1H), 6.94 (s, 1H), 6.99 (s, 1H), 7.52-7.59 (m, 2H),7.67 (d, J=3.2 Hz, 1H), 8.06 (s, 1H), 8.30-8.37 (m, 1H).

EXAMPLE 24 Synthesis of1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-6-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from6-allyl-7-hydroxy-2,2-dimethyl-4-oxochroman according to the methoddescribed in Example 22, (3) and (4).

¹H-NMR (DMSO-d₆) δ (ppm): 1.39 (s, 6H), 1.92-2.08 (m, 4H), 2.21-2.31 (m,2H), 2.45-2.56 (m, 2H), 2.65-2.75 (m, 2H), 2.69 (s, 2H), 3.06-3.15 (m,2H), 3.85 (s, 3H), 4.37-4.47 (m, 1H), 6.50 (d, J=3.2 Hz, 1H), 6.53 (s,1H), 7.20 (br.s, 1H), 7.50-7.60 (m, 2H), 7.53 (s, 1H), 7.67 (d, J=3.2Hz, 1H), 7.91 (br.s, 1H), 8.13 (s, 1H).

EXAMPLE 25 Synthesis of1-{1-[2-(5-methoxy-1-oxoindan-4-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from 5-hydroxy-1-indanone accordingto the method described in Example 22.

¹H-NMR (DMSO-d₆) δ (ppm): 1.93-2.10 (m, 4H), 2.24-2.34 (m, 2H),2.47-2.57 (m, 2H), 2.58-2.65 (m, 2H), 2.80-2.87 (m, 2H), 3.03-3.17 (m,4H), 3.91 (s, 3H), 4.38-4.47 (m, 1H), 6.51 (d, J=3.2 Hz, 1H), 7.10 (d,J=8.4 Hz, 1H), 7.21 (br.s, 1H), 7.51-7.61 (m, 3H), 7.68 (d, J=3.2 Hz,1H), 7.91 (br.s, 1H), 8.13 (s, 1H).

EXAMPLE 26 Synthesis of1-{1-[2-(6-methoxy-3-oxoindan-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from 5-hydroxy-1-indanone accordingto the method described in Example 22.

¹H-NMR (DMSO-d₆) δ (ppm): 1.92-2.07 (m, 4H), 2.21-2.32 (m, 2H),2.50-2.61 (m, 4H), 2.76-2.84 (m, 2H), 3.02-3.16 (m, 4H), 3.92 (s, 3H),4.36-4.47 (m, 1H), 6.50 (d, J=2.8 Hz, 1H), 7.13 (s, 1H), 7.21 (br.s,1H), 7.46 (s, 1H), 7.52-7.61 (m, 2H), 7.64-7.69 (m, 1H), 7.91 (br.s,1H), 8.13 (s, 1H).

EXAMPLE 27 Synthesis of1-{1-[2-(5-methoxy-2-methylbenzothiazol-4-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from 2-methyl-5-benzothiazoleaccording to the method described in Example 22.

¹H-NMR (DMSO-d₆) δ (ppm): 1.94-2.09 (m, 4H), 2.24-2.34 (m, 2H),2.55-2.63 (m, 2H), 2.78 (s, 3H), 3.13-3.30 (m, 4H), 3.88 (s, 3H),4.37-4.47 (m, 1H), 6.50 (d, J=3.2 Hz, 1H), 7.16 (d, J=8.8 Hz, 1H), 7.21(br.s, 1H), 7.53-7.61 (m, 2H), 7.67 (d, J=3.2 Hz, 1H), 7.81 (d, J=8.8Hz, 1H), 7.91 (br.s, 1H), 8.13 (s, 1H).

EXAMPLE 28 Synthesis of1-{1-[2-(5-methoxy-2-methylbenzothiazol-6-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from 2-methyl-5-benzothiazoleaccording to the method described in Example 22.

¹H-NMR (DMSO-d₆) δ (ppm): 1.93-2.09 (m, 4H), 2.23-2.32 (m, 2H),2.57-2.63 (m, 2H), 2.76 (s, 3H), 2.84-2.90 (m, 2H), 3.08-3.16 (m, 2H),3.88 (s, 3H), 4.37-4.48 (m, 1H), 6.50 (d, J=2.8 Hz, 1H), 7.20 (br.s,1H), 7.47 (s, 1H), 7.53-7.61 (m, 2H), 7.67 (d, J=2.8 Hz, 1H), 7.80 (s,1H), 7.91 (br.s, 1H), 8.13 (s, 1H).

EXAMPLE 29 Synthesis of1-{1-[2-(7-methoxyquinolin-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from 7-hydroxyquinoline accordingto the method described in Example 22.

¹H-NMR (DMSO-d₆) δ (ppm): 1.95-2.11 (m, 4H), 2.26-2.36 (m, 2H),2.54-2.63 (m, 2H), 3.17-3.25 (m, 2H), 3.40-3.47 (m, 2H), 3.99 (s, 3H),4.38-4.48 (m, 1H), 6.51 (d, J=3.2 Hz, 1H), 7.21 (br.s, 1H), 7.37 (dd,J=4.0, 8.0 Hz, 1H), 7.52-7.60 (m, 3H), 7.68 (d, J=3.2 Hz, 1H), 7.88 (d,J=9.2 Hz, 1H), 7.92 (br.s, 1H), 8.14 (s, 1H), 8.27 (dd, J=2.0, 8.0 Hz,1H), 8.89 (dd, J=2.0, 4.0 Hz, 1H).

EXAMPLE 30 Synthesis of1-{1-[2-(6-methoxyquinolin-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from 6-hydroxyquinoline accordingto the method described in Example 22.

¹H-NMR (DMSO-d₆) δ (ppm): 1.96-2.12 (m, 4H), 2.29-2.38 (m, 2H),2.48-2.58 (m, 2H), 3.17-3.30 (m, 4H), 3.98 (s, 3H), 4.39-4.50 (m, 1H),6.51 (d, J=3.6 Hz, 1H), 7.21 (br.s, 1H), 7.50-7.62 (m, 3H), 7.66-7.72(m, 2H), 7.92 (br.s, 1H), 7.95 (d, J=9.2 Hz, 1H), 8.14 (s, 1H), 8.42 (d,J=9.2 Hz, 1H), 8.77-8.79 (m, 1H).

EXAMPLE 31 Synthesis of1-{1-[2-(7-methoxy-2,3-dihydrobenz[1,4]dioxin-6-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from 6-hydroxy-1,4-benzodioxane(CAS#: 10288-72-9) according to the method described in Example 22.

¹H-NMR (DMSO-d₆) δ (ppm): 1.92-2.08 (m, 4H), 2.19-2.28 (m, 2H),2.45-2.54 (m, 2H), 2.61-2.67 (m, 2H), 3.05-3.12 (m, 2H), 3.70 (s, 3H),4.13-4.22 (m, 4H), 4.36-4.46 (m, 1H), 6.48 (s, 1H), 6.50 (d, J=3.2 Hz,1H), 6.69 (s, 1H), 7.21 (br.s, 1H), 7.54-7.60 (m, 2H), 7.67 (d, J=3.2Hz, 1H), 7.91 (br.s, 1H), 8.12 (s, 1H).

EXAMPLE 32 Synthesis of1-{1-[2-(6-methoxy-2,3-dihydrobenz[1,4]dioxin-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from 6-hydroxy-1,4-benzodioxane(CAS#: 10288-72-9) according to the method described in Example 22.

¹H-NMR (DMSO-d₆) δ (ppm): 1.92-2.09 (m, 4H), 2.19-2.30 (m, 2H),2.40-2.48 (m, 2H), 2.71-2.79 (m, 2H), 3.07-3.14 (m, 2H), 3.72 (s, 3H),4.13-4.19 (m, 2H), 4.23-4.28 (m, 2H), 4.37-4.46 (m, 1H), 6.47 (d, J=8.8Hz, 1H), 6.50 (d, J=3.2 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 7.21 (br.s,1H), 7.53-7.61 (m, 2H), 7.67 (d, J=3.2 Hz, 1H), 7.91 (br.s, 1H), 8.12(s, 1H).

EXAMPLE 33 Synthesis of1-{1-[2-(6-methoxy-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from6-hydroxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one (CAS#: 308110-07-8)according to the method described in Example 22.

¹H-NMR (DMSO-d₆) δ (ppm): 1.92-2.08 (m, 4H), 2.21-2.31 (m, 2H),2.50-2.57 (m, 2H), 2.74-2.81 (m, 2H), 2.94 (t, J=6.4 Hz, 2H), 3.07-3.14(m, 2H), 3.51 (t, J=6.4 Hz, 2H), 3.85 (s, 3H), 4.37-4.47 (m, 1H), 6.50(d, J=2.8 Hz, 1H), 6.86 (s, 1H), 7.21 (br.s, 1H), 7.53-7.61 (m, 2H),7.67 (s, 1H), 7.67 (d, J=2.8 Hz, 1H), 7.91 (br.s, 1H), 8.13 (s, 1H).

EXAMPLE 34

Synthesis of1-(1-(2-(6-methoxy-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)ethyl)piperidin-4-yl)-1H-indole-6-carboxamide

The subject compound was synthesized from6-hydroxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one (CAS#: 308110-07-8)according to the method described in Example 22.

¹H-NMR (DMSO-d₆) δ (ppm): 1.93-2.09 (m, 4H), 2.23-2.34 (m, 2H),2.38-2.48 (m, 2H), 2.78-2.87 (m, 2H), 2.94-3.03.(m, 2H), 3.00 (s, 3H),3.07-3.16 (m, 2H), 3.49-3.56 (m, 2H), 3.85 (s, 3H), 4.37-4.47 (m, 1H),6.48-6.53 (m, 1H), 6.97 (d, J=8.4 Hz, 1H), 7.21 (br.s, 1H), 7.53-7.61(m, 2H), 7.68 (d, J=3.2 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.91 (br.s,1H), 8.12 (s, 1H).

EXAMPLE 35 Synthesis of1-{1-[2-(7-methoxy-4-oxo-4H-chromen-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from7-hydroxy-4H-1-benzopyran-4-one (J. Med. Chem. 34 (1991) 1, 248)according to the method described in Example 22.

¹H-NMR (DMSO-d₆) δ (ppm): 1.95-2.07 (m, 4H), 2.25-2.35 (m, 2H),2.50-2.58 (m, 2H), 2.99-3.05 (m, 2H), 3.11-3.19 (m, 2H), 3.96 (s, 3H),4.38-4.48 (m, 1H), 6.27 (d, J=6.0 Hz, 1H), 6.50 (d, J=2.8 Hz, 1H), 7.21(br.s, 1H), 7.25 (d, J=9.2 Hz, 1H), 7.54-7.60 (m, 2H), 7.66 (d, J=3.2Hz, 1H), 7.91 (br.s, 1H), 7.94 (d, J=9.2 Hz, 1H), 8.13 (s, 1H), 8.31 (d,J=6.4 Hz, 1H).

EXAMPLE 36 Synthesis of1-{1-[2-(7-methoxy-2,3-dimethyl-4-oxo-4H-chromen-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) 2,3-Dimethyl-7-hydroxy-4H-1-benzopyran-4-one

The subject compound was synthesized from 2′,4′-dihydroxypropiophenonein accordance with Bull. Chem. Soc. Jpn., 67, 1972 (1994).

¹H-NMR (DMSO-d₆) δ (ppm): 1.91 (s, 3H), 2.36 (s, 3H), 6.76 (d, J=1.6 Hz,1H), 6.86 (dd, J=1.6, 8.8 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 10.64 (br.s,1H).

(2)1-{1-[2-(7-methoxy-2,3-dimethyl-4-oxo-4H-chromen-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from2,3-dimethyl-7-hydroxy-4H-1-benzopyran-4-one according to the methoddescribed in Example 22.

¹H-NMR (DMSO-d₆) δ (ppm): 1.92-2.07 (m, 4H), 1.94 (s, 3H), 2.27-2.36 (m,2H), 2.43 (s, 3H), 2.51-2.60 (m, 2H), 2.97-3.05 (m, 2H), 3.13-3.21 (m,2H), 3.95 (s, 3H), 4.38-4.48 (m, 1H), 6.50 (d, J=3.2 Hz, 1H), 7.19 (d,J=8.8 Hz, 1H), 7.21 (br.s, 1H), 7.53-7.60 (m, 2H), 7.67 (d, J=3.2 Hz,1H), 7.86-7.94 (m, 1H), 7.91 (d, J=8.8 Hz, 1H), 8.13 (s, 1H).

EXAMPLE 37 Synthesis of1-{1-[2-(7-methoxy-3,3-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) 7-Hydroxy-3,3-dimethyl-4-oxochromane

The subject compound was synthesized from resorcinol and 3-chloropivalicacid in accordance with J. Org. Chem. 1994, 59, 1216.

¹H-NMR (DMSO-d₆) δ (ppm): 1.06 (s, 6H), 4.14 (s, 2H), 6.31 (d, J=2.4 Hz,1H), 6.50 (dd, J=2.4, 8.8 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 10.53 (br.s,1H).

(2)1-{1-[2-(7-Methoxy-3,3-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from7-hydroxy-3,3-dimethyl-4-oxochromane according to the method describedin Example 22.

¹H-NMR (DMSO-d₆) δ (ppm): 1.09 (s, 6H), 1.92-2.08 (m, 4H), 2.20-2.30 (m,2H), 2.43-2.52 (m, 2H), 2.76-2.84 (m, 2H), 3.08-3.16 (m, 2H), 3.88 (s,3H), 4.23 (s, 2H), 4.37-4.46 (m, 1H), 6.50 (d, J=3.2 Hz, 1H), 6.82 (d,J=8.8 Hz, 1H), 7.21 (br.s, 1H), 7.54-7.61 (m, 2H), 7.65 (d, J=3.2 Hz,1H), 7.69 (d, J=8.8 Hz, 1H), 7.91 (br.s, 1H), 8.12 (s, 1H).

EXAMPLE 38 Synthesis of1-{1-[2-(6-methoxy-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide

The subject compound was synthesized from6-hydroxy-2-methyl-3,4-dihydro-2H-isoquinolin-1-one (CAS#: 308110-07-8)according to the methods described in Example 22, (1), (2) and (3), andExample 23, (5).

¹H-NMR (DMSO-d₆) δ (ppm): 1.92-2.08 (m, 4H), 2.23-2.31 (m, 2H),2.49-2.57 (m, 2H), 2.74-2.81 (m, 2H), 2.82 (d, J=4.4 Hz, 3H), 2.94 (t,J=6.4 Hz, 2H), 2.99 (s, 3H), 3.07-3.16 (m, 2H), 3.51 (t, J=6.4 Hz, 2H),3.86 (s, 3H), 4.36-4.46 (m, 1H), 6.50 (d, J=2.8 Hz, 1H), 6.87 (s, 1H),7.51-7.58 (m, 2H), 7.66 (d, J=2.8 Hz, 1H), 7.67 (s, 1H), 8.06 (3, 1H),8.30-8.37 (m, 1H).

EXAMPLE 39 Synthesis of1-{1-[2-(6-methoxy-methyl-oxo-1,4-dihydro-2H-benz[d][1,3]oxazin-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from7-allyl-6-methoxy-1-methyl-1,4-dihydrobenz[d][1,3]oxazin-2-one accordingto the method described in Example 20, (4).

¹H-NMR (DMSO-d₆) δ (ppm): 1.93-2.08-(m, 4H), 2.22-2.32 (m, 2H),2.52-2.61 (m, 2H), 2.76-2.83 (m, 2H), 3.08-3.15 (m, 2H), 3.26 (s, 3H),3.79 (s, 3H), 4.37-4.47 (m, 1H), 5.19 (s, 2H), 6.50 (d, J=3.2 Hz, 1H),6.94 (s, 1H), 6.99 (s, 1H), 7.21 (br.s, 1H), 7.54-7.60 (m, 2H), 7.67 (d,J=3.2 Hz, 1H), 7.91 (br.s, 1H), 8.12 (s, 1H).

EXAMPLE 40 Synthesis of1-{1-[2-(7-methoxy-2-methoxymethyl-2-methyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-1-H-indole-6-carboxamide

(1) 8-Allyl-7-methoxy-2-methoxymethyl-2-methyl-4-oxochromane

445 mg of 3′-allyl-2′-hydroxy-4′-methoxyacetophenone and 0.57 g ofmethoxyacetone were dissolved in 10 ml of toluene. Thereafter, 0.19 g ofpyrrolidine and 0.19 ml of acetic acid were added to the reactionsolution. Thereafter, the reaction solution was heated to reflux usingDean-Stark for 1 hour. Thereafter, the reaction solution was cooled to aroom temperature. 1.14 g of methoxyacetone, 0.38 g of pyrrolidine, and0.38 ml of acetic acid were added to the reaction solution, and theobtained mixture was further heated to reflux overnight. The reactionsolution was cooled to a room temperature and then concentrated under areduced pressure. The residue was diluted with ethyl acetate, and thensuccessively washed with 2 N hydrochloric acid, a 1 N sodium hydroxideaqueous solution, water, and a saturated sodium chloride aqueoussolution. The organic layer was dried over magnesium sulfate and thenconcentrated under a reduced pressure. The residue was purified bysilica gel column chromatography (hexane-ethyl acetate), so as to obtain194 mg of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.36 (s, 3H), 2.53 (d, J=16.0 Hz, 1H), 2.98 (d,J=16.0 Hz, 1H), 3.34-3.40 (m, 2H), 3.41 (s, 3H), 3.43 (d, J=8.8 Hz, 1H),3.55 (d, J=8.8 Hz, 1H), 3.88 (s, 3H), 4.92-5.03 (m, 2H), 5.84-5.95 (m,1H), 6.58 (d, J=9.2 Hz, 1H), 7.79 (d, J=9.2 Hz, 1H).

(2)1-{1-[2-(7-Methoxy-2-methoxymethyl-2-methyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from8-allyl-7-methoxy-2-methoxymethyl-2-methyl-4-oxochromane according tothe method described in Example 22, (4).

¹H-NMR (DMSO-d₆) δ (ppm): 1.33 (s, 3H), 1.92-2.10 (m, 4H), 2.23-2.34 (m,2H), 2.40-2;-52 (m, 2H), 2.61 (d, J=16.8 Hz, 1H), 2.74-2.82 (m, 2H),2.86 (d, J=16.8 Hz, 1H), 3.07-3.17 (m, 2H), 3.31 (s, 3H), 3.49 (s, 2H),3.87 (s, 3H), 4.37-4.48 (m, 1H), 6.51 (d, J=3.2 Hz, 1H), 6.75 (d, J=8.8Hz, 1H), 7.21 (br.s, 1H), 7.53-7.61 (m, 2H), 7.64 (d, J=8.8 Hz, 1H),7.68 (d, J=3.2 Hz, 1H), 7.91 (br.s, 1H), 8.13 (s, 1H).

EXAMPLE 41 Synthesis of1-{1-[2-(7-methoxy-4-oxo-spiro(chroman-2,1′-cyclopentan)-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from3′-allyl-2′-hydroxy-4′-methoxyacetophenone according to the methoddescribed in Example 40.

¹H-NMR (DMSO-d₆) δ (ppm): 1.60-1.90 (m, 6H), 1.90-2.10 (m, 6H),2.22-2.32 (m, 2H), 2.40-2.48 (m, 2H), 2.73-2.81 (m, 2H), 2.83 (s, 2H),3.08-3.15 (m, 2H), 3.88 (s, 3H), 4.37-4.48 (m, 1H), 6.51 (d, J=3.2 Hz,1H), 6.60 (d, J=8.8 Hz, 1H), 7.21 (br.s, 1H), 7.53-7.61 (m, 2H), 7.66(d, J=8.8 Hz, 1H), 7.68 (d, J=3.2 Hz, 1H), 7.91 (br.s, 1H), 8.14 (s,1H).

EXAMPLE 42 Synthesis of1-{1-[2-(5,7-dimethoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) 5,7-Dihydroxy-2,2-dimethyl-4-oxochromane

40 ml of methanesulfonic acid was added to 1.99 g of diphosphoruspentoxide under nitrogen atmosphere. Thereafter, a mixture consisting of3.15 g of 1,3,5-trihydroxybenzene and 3,3-dimethylacrylic acid was addedto the reaction solution at 70° C. The reaction solution was stirred at70° C. for 30 minutes and then cooled to a room temperature. Thereaction solution was added to ice water, followed by extraction withethyl acetate. The extract was washed with water and a saturated sodiumchloride aqueous solution. The organic layer was dried over magnesiumsulfate and then concentrated under a reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate), soas to obtain 2.81 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.43 (s, 6H), 2.68 (s, 2H), 5.53 (br.s, 1H),5.87 (d,-J=2.4 Hz, 1H), 5.93 (d, J=2.4 Hz, 1H), 12.03 (s, 1H)

(2) 7-Allyloxy-5-hydroxy-2,2-dimethyl-4-oxochromane

2.81 g of 5,7-dihydroxy-2,2-dimethyl-4-oxochromane was dissolved in 60ml of acetone. Thereafter, 2.05 g of potassium carbonate and 1.80 g ofallyl bromide were added to the reaction solution, and the obtainedmixture was then stirred at room temperature for 24 hours. Thereafter,0.20 g of potassium carbonate and 0.18 g of allyl bromide were furtheradded to the reaction solution, and the obtained mixture was thenstirred at room temperature for 10 hours. Thereafter, 0.20 g ofpotassium carbonate and 0.18 g of allyl bromide were further added tothe reaction solution, and the obtained mixture was then stirred at roomtemperature for 14 hours. Thereafter, 0.20 g of potassium carbonate and0.18 g of allyl bromide were further added to the reaction solution, andthe obtained mixture was then stirred at room temperature for 7 hours.The reaction solution was concentrated under a reduced pressure, and theresidue was diluted with ethyl acetate. The resultant product was washedwith water and a saturated sodium chloride aqueous solution. The organiclayer was dried over magnesium sulfate and then concentrated under areduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate), so as to obtain 2.90 g of thesubject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.46 (s, 6H), 2.68 (s, 2H), 4.52-4.57 (m, 2H),5.29-5.35 (m, 1H), 5.37-5.45 (m, 1H), 5.94-6.07 (m, 3H), 11.99 (s, 1H).

(3) 7-Allyloxy-5-methoxy-2,2-dimethyl-4-oxochromane

2.90 g of 7-allyloxy-5-hydroxy-2,2-dimethyl-4-oxochromane was dissolvedin 50 ml of N,N-dimethylformamide. Thereafter, 2.42 g of potassiumcarbonate and 2.32 g of iodomethane were added to the reaction solution,and the obtained mixture was then stirred at room temperature for 3days. Thereafter, the reaction solution was diluted with ethyl acetate.The resultant product was washed with a saturated sodium chlorideaqueous solution. The organic layer was dried over magnesium sulfate andthen concentrated under a reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate), so as to obtain2.79 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.43 (s, 6H), 2.64 (s, 2H), 3.87 (s, 3H), 4.54(d, J=5.6 Hz, 2H), 5.33 (dd, J=1.6, 10.0, 1H), 5.42 (dd, J=1.6, 17.2 Hz,1H), 5.98-6.10 (m, 1H), 6.03 (d, J=2.0 Hz, 1H), 6.06 (d, J=2.0 Hz, 1H).

(4)1-{1-[2-(5,7-Dimethoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from7-allyloxy-5-methoxy-2,2-dimethyl-4-oxochromane according to-the methods.described in Example 22, (2), (3) and (4).

¹H-NMR (DMSO-d₆) δ (ppm): 1.37 (s, 6H), 1.92-2.10 (m, 4H), 2.20-2.31 (m,2H), 2.35-2.45 (m, 2H), 2.59 (s, 2H), 2.64-2.73 (m, 2H), 3.07-3.16 (m,2H), 3.81 (s, 3H), 3.89 (s, 3H), 4.37-4.47 (m, 1H), 6.28 (s, 1H), 6.50(d, J=3.2 Hz, 1H), 7.21 (br.s, 1H), 7.53-7.61 (m, 2H), 7.67 (d, J=3.2Hz, 1H), 7.91 (br.s, 1H), 8.13 (s, 1H).

EXAMPLE 43 Synthesis of1-{1-[2-(7-methoxy-4-oxo-spiro(chroman-2,4′-oxan)-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) 7-Hydroxy-4-oxo-spiro(chroman-2,4′-oxan)

The subject compound was synthesized from resorcinol and(tetrahydropyran-4-yliden)acetic acid according to the method describedin Example 42, (1).

¹H-NMR (CDCl₃) δ (ppm): 1.72-1.82 (m, 2H), 1.94-2.02 (m, 2H), 2.69 (s,2H), 3.73-3.89 (m, 4H), 6.01 (br.s, 1H), 6.43 (d, J=2.4 Hz, 1H), 6.49(dd, J=2.4, 8.4 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H).

(2)1-{1-[2-(7-Methoxy-4-oxo-spiro(chroman-2,4′-oxan)-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from7-hydroxy-4-oxo-spiro(chroman-2,4′-oxane) according to the methoddescribed in Example 22.

¹H-NMR (DMSO-d₆) δ (ppm): 1.70-1.90 (m, 4H), 1.94-2.12 (m, 4H),2.27-2.36 (m, 2H), 2.47-2.57 (m, 2H), 2.77 (s, 2H), 2.83-2.92 (m, 2H),3.10-3.20 (m, 2H), 3.67-3.77 (m, 4H), 3.89 (s, 3H), 4.40-4.50 (m, 1H),6.51 (d, J=3.2 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 7.21 (br.s, 1H),7.54-7.61 (m, 2H), 7.64-7.71 (m, 2H), 7.91 (br.s, 1H), 8.15 (s, 1H).

EXAMPLE 44 Synthesis of1-{1-[2-(2-methoxynaphthalen-1-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

While cooling on ice, 0.61 g of potassium t-butoxide was added to 20 mlof a tetrahydrofuran suspension containing 2.28 g of(methoxymethyl)triphenylphosphonium chloride under nitrogen atmosphere.The obtained mixture was stirred for 5 minutes. Thereafter, 600 mg of2-methoxy-1-naphthaldehyde was added to the reaction solution whilecooling on ice. The obtained mixture was stirred at the same temperaturefor 20 minutes. The reaction solution was diluted with ethyl acetate,and then washed with water and a saturated sodium chloride aqueoussolution. The organic layer was dried over magnesium sulfate and thenconcentrated under a reduced pressure. The residue was purified bysilica gel column chromatography (hexane-ethyl acetate), so as to obtain667 mg of 2-methoxy-1-(2-methoxyvinyl)naphthalene containing a smallamount of triphenylphosphine. This compound was used in the nextreaction without further purification.

120 mg of 2-methoxy-1-(2-methoxyvinyl)naphthalene was dissolved in 4 mlof 2 N hydrochloric acid-tetrahydrofuran (1:1). The obtained mixture wasthen stirred at 70° C. for 2 hours. The reaction solution was cooled toa room temperature and then diluted with ethyl acetate. The resultantproduct was washed with water and a saturated sodium chloride aqueoussolution. The organic layer was dried over-magnesium sulfate and thenconcentrated under a reduced pressure, so as to obtain 115 mg of(2-methoxynaphthalen-1-yl)acetaldehyde. This compound was used in thefollowing reaction without further purification.

70 mg of 1-(piperidin-4-yl)-1H-indole-6-carboxamide and 115 mg of(2-methoxynaphthalen-1-yl)acetaldehyde were dissolved in 2 ml oftetrahydrofuran. Thereafter, 0.03 ml of acetic acid and 91 mg of sodiumtriacetoxyborohydride were added to the reaction solution, and theobtained mixture was then stirred at room temperature overnight.Thereafter, a saturated sodium bicarbonate aqueous solution was added tothe reaction solution, and then extracted with chloroform. The extractwas dried over magnesium sulfate and then concentrated under a reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate-methanol), so as to obtain 72 mg of the subject compound.

¹H-NMR (DMSO-d₆) δ (ppm): 1.98-2.14 (m, 4H), 2.30-2.40 (m, 2H),2.50-2.60 (m, 2H), 3.18-3.38 (m, 4H), 3.95 (s, 3H), 4.40-4.50 (m, 1H),6.52 (d, J=3.2 Hz, 1H), 7.22 (br.s, 1H), 7.33-7.40 (m, 1H), 7.45 (d,J=9.2 Hz, 1H), 7.50-7.62 (m, 3H), 7.70 (d, J=3.2 Hz, 1H), 7.82-7.90 (m,2H), 7.92 (br.s, 1H), 7.97 (d, J=8.4 Hz, 1H), 8.15 (s, 1H)

EXAMPLE 45 Synthesis of1-{1-[2-(3-methoxynaphthalen-2-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from3-methoxy-2-naphthalenecalbaldehyde (CAS#: 56679-88-0) according to themethod described in Example 44.

¹H-NMR (DMSO-d₆) δ (ppm): 1.93-2.10 (m, 4H), 2.25-2.35 (m, 2H),2.63-2.70 (m, 2H), 2.90-2.96 (m, 2H), 3.11-3.19 (m, 2H), 3.93 (s, 3H),4.38-4.48 (m, 1H), 6.50 (d, J=3.2 Hz, 1H), 7.21 (br.s, 1H), 7.28-7.35(m, 2H), 7.37-7.44 (m, 1H), 7.53-7.60 (m, 2H), 7.68 (d, J=3.2 Hz, 1H),7.72 (s, 1H), 7.75-7.81 (m, 2H), 7.92 (br.s, 1H), 8.14 (s, 1H).

EXAMPLE 46 Synthesis of1-{1-[2-(4-hydroxy-7-methoxychroman-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

52 mg of1-(1-(2-(7-methoxy-4-oxo-4H-chromen-8-yl)ethyl)piperidin-4-yl)-1H-indole-6-carboxamidewas dissolved in 6.ml of methanol-tetrahydrofuran (1:1). Thereafter, 5mg of sodium borohydride was added to the reaction solution whilecooling on ice. The obtained mixture was then stirred at roomtemperature for 2 hours. Thereafter, 5 mg of sodium borohydride wasadded to the reaction solution, and further, 5 mg each of sodiumborohydride was added thereto 2 hours and 4 hours later. Thereafter, thereaction solution was stirred at the same temperature overnight. Asaturated sodium bicarbonate aqueous solution was added to the reactionsolution, followed by extraction with chloroform. The extract was driedover magnesium sulfate and then concentrated under a reduced pressure.The residue was purified by NH silica gel column chromatography (ethylacetate-methanol), so as to obtain 30 mg of the subject compound.

¹H-NMR (DMSO-d₆) δ (ppm): 1.80-1.88 (m, 1H), 1.90-2.10 (m, 5H),2.19-2.28 (m, 2H), 2.36-2.44 (m, 2H), 2.69-2.77 (m, 2H), 3.07-3.15 (m,2H), 3.76 (s, 3H), 4.16-4.24 (m, 2H), 4.37-4.46 (m, 1H), 4.55-4.60 (m,1H), 5.17 (d, J=5.2 Hz, 1H), 6.50 (d, J=3.2 Hz, 1H), 6.56 (d, J=8.8 Hz,1H), 7.11 (d, J=8.8 Hz, 1H), 7.21 (br.s, 1H), 7.54-7.60 (m, 2H), 7.67(d, J=3.2 Hz, 1H), 7.91 (br.s, 1H), 8.12 (s, 1H).

EXAMPLE 47 Synthesis of1-{1-[2-(7-methoxy-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

42 mg of1-(1-(2-(7-methoxy-4-oxo-4H-chromen-8-yl)ethyl)piperidin-4-yl)-1H-indole-6-carboxamidewas dissolved in 3 ml of methanol. Thereafter, 15 mg of 10% palladiumcarbon was added to the reaction solution. The obtained-mixture was thenstirred at room temperature for 15 hours under hydrogen atmosphere.Thereafter, 15 mg of 10% palladium carbon was further added to thereaction solution. The obtained mixture was then stirred at the sametemperature for 4 hours. Thereafter, palladium carbon was removed byfiltration, and the filtrate was concentrated under a reduced pressure.The residue was purified by NH silica gel column chromatography (ethylacetate), so as to obtain 20 mg of the subject compound.

¹H-NMR (DMSO-d₆) δ (ppm): 1.93-2.08 (m, 4H), 2.20-2.30 (m, 2H),2.42-2.50 (m, 2H), 2.72 (t, J=6.3 Hz, 2H), 2.74-2.82 (m, 2H), 3.08-3.16(m, 2H), 3.88 (s, 3H), 4.37-4.47 (m, 1H), 4.54 (t, J=6.3 Hz, 2H), 6.50(d, J=2.8 Hz, 1H), 6.80 (d, J=8.8 Hz, 1H), 7.21 (br.s, 1H), 7.55-7.60(m,2H), 7.67(d, J=2.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.91 (br.s, 1H),8.12 (s, 1H).

EXAMPLE 48 Synthesis of1-{1-[2-(4-hydroxy-7-methoxy-2,2-dimethylchroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide

259 mg of1-(1-(2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl)piperidin-4-yl)-N-methyl-1H-indole-6-carboxamidewas dissolved in 5 ml of methanol. Thereafter, 60 mg of sodiumborohydride was added to the reaction solution while cooling on ice. Theobtained mixture was then stirred at room temperature overnight.Thereafter, a saturated sodium bicarbonate aqueous solution was added tothe reaction solution, followed by extraction with methylene chloride.The extract was dried over magnesium sulfate and then concentrated undera reduced pressure. The residue was purified by NH silica gel columnchromatography (ethyl acetate) and then purified by silica gel columnchromatography (ethyl acetate-methanol), so as to obtain 216 mg of thesubject compound.

¹H-NMR (DMSO-d₆) δ (ppm): 1.24 (s, 3H), 1.37 (s, 3H), 1.92-2.00 (m, 5H),2.26 (t, J=11.2 Hz, 2H), 2.37-2.46 (m, 2H), 2.68-2.77 (m, 2H), 2.82 (d,J=4.4 Hz, 3H), 3.07-3.16 (m, 2H), 3.75 (s, 3H), 4.36-4.45 (m, 1H),4.60-4.66 (m, 1H), 5.17 (d, J=6.0 Hz, 1H), 6.50 (d, J=3.2 Hz, 1H), 6.55(d, J=8.8 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 7.51-7.58 (m, 2H), 7.66 (d,J=3.2 Hz, 1H), 8.06. (s, 1H), 8.19-8.36 (m, 1H).

EXAMPLE 49 Synthesis of1-{1-[2-(1-hydroxy-5-methoxyindan-4-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from1-(1-(2-(5-methoxy-1-oxoindan-4-yl)ethyl)piperidin-4-yl)-1H-indole-6-carboxamideaccording to the method described in Example 48.

¹H-NMR (DMSO-d₆) δ (ppm): 1.72-1.83 (m, 1H), 1.90-2.10 (m, 4H),2.20-2.37 (m, 3H), 2.40-2.50 (m, 2H), 2.62-2.78 (m, 3H), 2.87-2.97 (m,1H), 3.05-3.16 (m, 2H), 3.77 (s, 3H), 4.36-4.47 (m, 1H), 4.96-5.05 (m,2H), 6.47-6.53 (m, 1H), 6.82 (d, J=8.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H),7.21 (br.s, 1H), 7.52-7.62 (m, 2H), 7.64-7.70 (m, 1H), 7.91 (br.s, 1H),8.12 (s, 1H).

EXAMPLE 50 Synthesis of1-{l-[2-(3-hydroxy-6-methoxyindan-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from1-(1-(2-(6-methoxy-3-oxoindan-5-yl)ethyl)piperidin-4-yl)-1H-indole-6-carboxamideaccording to the method described in Example 48.

¹H-NMR (DMSO-d₆) δ (ppm): 1.72-1.82 (m, 1H), 1.90-2.10 (m, 4H),2.20-2.36 (m, 3H), 2.44-2.57 (m, 2H), 2.63-2.79 (m, 3H), 2.85-2.94 (m,1H), 3.07-3.16 (m, 2H), 3.78 (s, 3H), 4.37-4.48 (m, 1H), 4.98 (dd,J=5.6, 12.0 Hz, 1H), 5.03 (d, J=5.6 Hz, 1H), 6.51 (d, J=3.2 Hz, 1H),6.82 (3, 1H), 7.11 (s, 1H), 7.21 (br.s, 1H), 7.53-7.62 (m, 2H), 7.67 (d,J=3.2 Hz, 1H), 7.92 (br.s, 1H), 8.13 (s, 1H).

EXAMPLE 51 Synthesis of1-{1-[2-(6-methoxyquinolin-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) 1-Allyl-2-methoxy-5-nitrobenzene

The subject compound was synthesized from 2-allylphenol according to themethod described in Example 23, (1).

¹H-NMR (CDCl₃) δ (ppm): 3.42 (d, J=6.8 Hz, 2H), 3.94 (s, 3H), 5.07-5.17(m, 2H), 5.91-6.03 (m, 1H), 6.90 (d, J=9.2 Hz, 1H), 8.06 (d, J=2.4 Hz,1H), 8.15 (dd, J=2.4, 9.2 Hz, 1H).

(2) 3-Allyl-4-methoxyaniline

15.0 g of 1-allyl-2-methoxy-5-nitrobenzene, 33.4 g of ammonium chloride,and 17.5 g of iron were suspended in 270 ml of ethanol and 55 ml ofwater. The reaction solution was heated to reflux for 1 hour.Thereafter, the reaction solution was cooled to a room temperature, andinsoluble matters were then removed by filtration. The filtrate wasconcentrated under a reduced pressure. The residue was diluted withethyl acetate and then washed with a saturated sodium bicarbonateaqueous solution and a saturated sodium chloride aqueous solution. Theorganic layer was dried over magnesium sulfate and then concentratedunder a reduced pressure. The residue was purified by silica gel columnchromatography (hexane-ethyl acetate), so as to obtain 11.1 g of thesubject compound.

¹H-NMR (CDCl₃) δ (ppm): 3.32 (d, J=6.4 Hz, 2H), 3.39 (br.s, 2H), 3.76(s, 3H), 5.00-5.10 (m, 2H), 5.91-6.03 (m, 1H), 6.51-6.57 (m, 2H),6.67-6.73 (m, 1H).

(3) 6-Methoxyquinoline-7-carbaldehyde

6-methoxy-7-(1-propenyl)quinoline with an isomerized double bond wassynthesized from 3-allyl-4-methoxyaniline in accordance withHeterocycles, Vol. 54, No. 1, 105 (2001) (wherein isomerization wascarried out when7-allyl-1-methanesulfonyl-6-methoxy-1,2-dihydroquinoline was allowed toreact with potassium hydroxide at 80° C. in dimethyl sulfoxide).

1.41 g of AD-mix-a and 93 mg of methanesulfonamide were dissolved in 12ml of t-butanol-water (1:1). Thereafter, 195 mg of6-methoxy-7-(1-propenyl)quinoline was added to the reaction solution,and the obtained mixture was then stirred overnight. Thereafter, 2.0 gof sodium sulfite was added to the reaction solution while cooling onice, and the obtained mixture was stirred at room temperature for 30minutes. Thereafter, a saturated sodium chloride aqueous solution wasadded to the reaction solution, followed by extraction of methylenechloride. The extract was then washed with a 2 N potassium hydroxideaqueous solution. The organic layer was dried over magnesium sulfate andthen concentrated under a reduced pressure, so as to obtain 236 mg of1-(6-methoxyquinolin-7-yl)propane-1,2-diol. This compound was used inthe following reaction, without further purification.

236 mg of 1-(6-methoxyquinolin-7-yl)propane-1,2-diol was dissolved in 8ml of tetrahydrofuran and 3 ml of methanol. Thereafter, 4 ml of watercontaining 0.43 g of sodium metaperiodate was added to the reactionsolution while cooling on ice. The obtained mixture was stirred at roomtemperature for 1 hour. The reaction solution was diluted with ethylacetate, and then washed with water and a saturated sodium chlorideaqueous solution. The organic layer was dried over magnesium sulfate andthen concentrated under a reduced pressure. The residue was purified bysilica gel column chromatography (hexane-ethyl acetate), so as to obtain149 mg of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 4.06 (s, 3H), 7.18 (s, 1H), 7.44 (dd, J=4.4, 7.6Hz, 1H), 8.05-8.11 (m, 1H), 8.57 (s, 1H), 8.84-8.89 (m, 1H), 10.61-10.64(m, 1H).

(4)1-{1-[2-(6-Methoxyquinolin-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from6-methoxyquinoline-7-carbaldehyde according to the method described inExample 44.

¹H-NMR (DMSO-d₆) δ (ppm): 1.94-2.10 (m, 4H), 2.27-2.86 (m, 2H),2.66-2.73 (m, 2H), 2.96-3.02 (m, 2H), 3.12-3.20 (m, 2H), 3.96 (s, 3H),4.39-4.49 (m, 1H), 6.50 (d, J=3.2 Hz, 1H), 7.21 (br.s, 1H), 7.35 (s,1H), 7.43 (dd, J=4.4, 8.4 Hz, 1H), 7.53-7.61 (m, 2H), 7.68 (d, J=3.2 Hz,1H), 7.84 (s, 1H), 7.92 (br.s, 1H), 8.14 (s, 1H), 8.20-8.26 (m, 1H),8.71 (dd, J=1.2, 4.4 Hz, 1H).

EXAMPLE 52 Synthesis of1-{1-[2-(1-acetyl-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) 7-[2-(1,4-Dioxa-8-azaspiro[4.5]decan-8-yl)ethyl]-6-methoxyquinolin

While cooling on ice, 0.82 g of potassium t-butoxide was added to 20 mlof a tetrahydrofuran suspension containing 2.50 g of(methoxymethyl)triphenylphosphonium chloride under nitrogen atmosphere.The obtained mixture was then stirred at the same temperature for 10minutes. Thereafter, 3 ml of a tetrahydrofuran solution containing 545mg of 6-methoxyquinoline-7-carbaldehyde was added to the reactionsolution while cooling on ice, and the obtained mixture was then stirredat the same temperature for 15 minutes. Thereafter, the reactionsolution was diluted with ethyl acetate, and then washed with water anda saturated sodium chloride aqueous solution. The organic layer wasdried over magnesium sulfate and then concentrated under a reducedpressure. The residue was purified by NH silica gel columnchromatography (hexane-ethyl acetate), so as to obtain 1.41 g of6-methoxy-7-(2-methoxyvinyl)quinoline containing triphenylphosphineoxide. This compound was used in the next reaction without furtherpurification.

1.41 g of 6-methoxy-7-(2-methoxyvinyl)quinoline was dissolved in 40 mlof 2 N hydrochloric acid-tetrahydrofuran (1:1), and the obtained mixturewas then stirred at 70° C. for 2 hours. The reaction solution was cooledto a room temperature. It was diluted with ethyl acetate and then washedwith a saturated sodium bicarbonate aqueous solution and a saturatedsodium chloride aqueous solution. The organic layer was dried overmagnesium sulfate and then concentrated under a reduced pressure, so asto obtain 1.45 g of (6-methoxyquinolin-7-yl)acetaldehyde containingtriphenylphosphine oxide. This compound was used in the followingreaction without further purification.

1.45 g of (6-methoxyquinolin-7-yl)acetaldehyde and 0.63 g of1,4-dioxa-8-azaspiro[4.5]decane were dissolved in 20 ml of methylenechloride. Thereafter, 0.42 ml of acetic acid and 0.74 g of sodiumtriacetoxyborohydride were added to the reaction solution, and theobtained mixture was then stirred at room temperature for 3 hours.Thereafter, a saturated sodium bicarbonate aqueous solution was added tothe reaction solution, followed by extraction with methylene chloride.The extract was dried over magnesium sulfate and then concentrated undera reduced pressure. The residue was purified by silica gel columnchromatography (chloroform-methanol), so as to obtain 445 mg of thesubject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.75-1.86 (m, 4H), 2.59-2.77 (m, 6H), 2.97-3.07(m, 2H), 3.94 (s, 3H), 3.97 (s, 4H), 7.00 (s, 1H), 7.29 (dd, J=4.4, 8.4Hz, 1H), 7.84 (s, 1H), 8.01 (dd, J=1.6, 8.4 Hz, 1H), 8.72 (dd, J=1.6,4.4 Hz, 1H).

(2)1-acetyl-7-[2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl]-6-methoxy-1,2,3,4-tetrahydroquinoline

445 mg of7-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxyquinoline wasdissolved in 10 ml of methanol. Thereafter, 100 mg of 10% palladiumcarbon was added to the reaction solution. The obtained mixture wasstirred for 6 hours under a 4 kg/cm² of hydrogen atmosphere. Thereafter,palladium carbon was removed by filtration, and the filtrate wasconcentrated under a reduced pressure. The reaction solution was stirredunder the same above conditions for 10 hours 3 times, and then, it wasconcentrated under a reduced pressure. A saturated sodium bicarbonateaqueous solution was added to the residue, followed by extraction withchloroform. The extract was dried over magnesium sulfate and thenconcentrated under a reduced pressure, so as to obtain 459 mg of7-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxy-1,2,3,4-tetrahydroquinoline.This compound was used in the next reaction without furtherpurification.

3 ml of acetic anhydride and 3 ml of pyridine were added to 251 mg of7-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxy-1,2,3,4-tetrahydroquinoline,and the obtained mixture was then stirred at room temperature for 90minutes. The reaction solution was concentrated under a reducedpressure. The residue was diluted with ethyl acetate and then washedwith water and a saturated sodium chloride aqueous solution. The organiclayer was dried over magnesium sulfate and then concentrated under areduced pressure. The residue was purified by NH silica gel columnchromatography (hexane-ethyl acetate) and then by silica gel columnchromatography (ethyl acetate-methanol), so as to obtain 162 mg of thesubject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.73-1.83 (m, 4H), 1.88-1.97 (m, 2H), 2.18(br.s, 3H), 2.54-2.73 (m, 8H), 2.75-2.84 (m, 2H), 3.70-3.80 (m, 2H),3.78 (s, 3H), 3.95 (s, 4H), 6.60 (s, 1H), 6.88 (br.s, 1H).

(3)1-{1-[2-(1-Acetyl-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

162 mg of1-acetyl-7-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxy-1,2,3,4-tetrahydroquinolinewas dissolved in 6 ml of 2 N hydrochloric acid-tetrahydrofuran (1:1),and the reaction solution was then stirred at 70° C. for 10 hours. Thereaction solution was cooled to a room temperature, and a saturatedsodium bicarbonate aqueous solution was added to the reaction solution,followed by extraction with methylene chloride. The extract was driedover magnesium sulfate and then concentrated under a reduced pressure,so as to obtain 127 mg of1-(2-(1-acetyl-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperidin-4-one.This compound was used in the following reaction without furtherpurification.

172 mg of 3-amino-4-(2,2-dimethoxyethyl)benzamide and 127 mg of1-(2-(1-acetyl-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperidin-4-onewere dissolved in 5 ml of acetic acid. Thereafter, 0.65 g of sodiumsulfate was added to the reaction solution, and the obtained mixture wasthen stirred at room temperature for 1 hour. Thereafter, 0.16 g ofsodium triacetoxyborohydride was added to the reaction solution, and theobtained mixture was then stirred for 1 hour. Thereafter, 5 ml of waterwas added thereto, and the obtained mixture was then stirred at 100° C.for 2 hours. The reaction solution was cooled to a room temperature, andit was then concentrated under a reduced pressure. A saturated sodiumbicarbonate aqueous solution was added to the residue, followed byextraction with chloroform. The extract was dried over magnesium sulfateand then concentrated under a reduced pressure. The residue was purifiedby silica gel column chromatography (chloroform-methanol) and NH silicagel column chromatography (ethyl acetate-methanol), so as to obtain 146mg of the subject compound.

¹H-NMR (DMSO-d₆) δ (ppm): 1.78-1.89 (m, 2H), 1.91-2.06 (m, 4H), 2.14 (s,3H), 2.19-2.30 (m, 2H), 2.47-2.57 (m, 2H), 2.63-2.77 (m, 4H), 3.06-3.13(m, 2H), 3.63 (t, J=6.4 Hz, 2H), 3.78 (s, 3H), 4.37-4.46 (m, 1H), 6.50(d, J=2.8 Hz, 1H), 6.78 (br.s, 1H), 7.06-7.26 (m, 2H), 7.53-7.60 (m,2H), 7.65 (d, J=2.8 Hz, 1H), 7.91 (br.s, 1H), 8.12 (s, 1H).

EXAMPLE 53 Synthesis of1-{1-[2-(6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1)7-[2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl]-6-methoxy-1-methyl-1,2,3,4-tetrahydroquinoline

445 mg of7-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxyquinoline wasdissolved in 10 ml of methanol. Thereafter, 100 mg of 10% palladiumcarbon was added to the reaction solution. The obtained mixture wasstirred for 6 hours under a 4 kg/cm² of hydrogen atmosphere. Palladiumcarbon was removed by filtration, followed by concentration under areduced pressure. The reaction solution was stirred under the sameconditions for 10 hours 3 times, followed by concentration under areduced pressure. A saturated sodium bicarbonate aqueous solution wasadded to the residue, followed by extraction with chloroform. Theextract was dried over magnesium sulfate and then concentrated under areduced pressure, so as to obtain 459 mg of7-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxy-1,2,3,4-tetrahydroquinoline.This compound was used in the following reaction without furtherpurification. 196 mg of7-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxy-1,2,3,4-tetrahydroquinolinewas dissolved in 5 ml of acetonitrile. Thereafter, 1 ml of 37% formalin,190 mg of sodium cyanoborohydride, and 0.15 ml acetic acid were added tothe reaction solution, and the obtained mixture was then stirred at roomtemperature for 1 hour. Thereafter, the reaction solution was dilutedwith ethyl acetate, and then washed with a saturated sodium bicarbonateaqueous solution and a saturated sodium chloride aqueous solution. Theorganic layer was dried over magnesium sulfate and then concentratedunder a reduced pressure. The residue was purified by NH silica gelcolumn chromatography (hexane-ethyl acetate), so as to obtain 100 mg ofthe subject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.52-1.63 (m, 3H), 1.75-1.88 (m, 3H), 1.94-2.01(m, 2H), 2.52-2.86 (m, 8H), 2.81 (s, 3H), 3.07-3.12 (m, 2H), 3.72 (s,3H), 3.97 (s, 4H), 6.48 (s, 1H), 6.51 (s, 1H).

(2)1-{1-[2-(6-Methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]piperidin-4-yl)-1H-indole-6-carboxamide

100 mg of7-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolinewas dissolved in 6 ml of 2 N hydrochloric acid-tetrahydrofuran (1:1).The reaction solution was stirred at 70° C. for 7 hours. The reactionsolution was cooled to a room temperature. Thereafter, a saturatedsodium bicarbonate aqueous solution was added to the reaction solution,followed by extraction with methylene chloride. The extract was driedover magnesium sulfate and then concentrated under a reduced pressure,so as to obtain 87 mg of1-(2-(6-methoxy-l-methyl-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperidin-4-one.This compound was used in the following reaction without furtherpurification.

129 mg of 3-amino-4-(2,2-dimethoxyethyl)benzamide and 87 mg of1-(2-(6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperidin-4-onewere dissolved in 4 ml of acetic acid. Thereafter, 0.49 g of sodiumsulfate was added to the reaction solution, and the obtained mixture wasthen stirred at room temperature for 1 hour. Thereafter, 0.12 g ofsodium triacetoxyborohydride was added to the reaction solution, and theobtained -mixture was then stirred at room temperature for 1 hour.Thereafter, 4 ml of water was further added to the reaction solution,and the obtained mixture was then stirred at 100° C. for 2 hours. Thereaction solution was cooled to a room temperature, followed byconcentration under a reduced pressure. A saturated sodium bicarbonateaqueous solution was added to the residue, followed by extraction withchloroform. The extract was dried over magnesium sulfate and thenconcentrated under a reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate-methanol) and by NHsilica gel column chromatography (ethyl acetate), so as to obtain 70 mgof the subject compound.

¹H-NMR (DMSO-d₆) δ (ppm.): 1.83-1.91 (m, 2H), 1.92-2.08 (m, 4H),2.20-2.29 (m, 2H), 2.47-2.54 (m, 2H), 2.63-2.71 (m, 4H), 2.76 (s, 3H),3.02-3.13 (m, 4H), 3.68 (s, 3H), 4.37-4.46 (m, 1H), 6.48 (s, 1H), 6.50(d, J=3.2 Hz, 1H), 6.56 (s, 1H), 7.21 (br.s, 1H), 7.53-7.61 (m, 2H),7.67 (d, J=3.2 Hz, 1H), 7.91 (br.s, 1H), 8.12 (s, 1H).

EXAMPLE 54

Synthesis of1-{1-[2-(1-acetyl-6-methoxy-1,2,3,4-tetrahydroquinolin-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) 5-Allyl-6-methoxyquinoline

The subject compound was synthesized from 6-hydroxyquinoline accordingto the methods described in Example 22, (1), (2), and (3).

¹H-NMR (CDCl₃) δ (ppm): 3.80-3.85 (m, 2H), 3.97 (s, 3H), 4.87-4.95 (m,1H), 4.97-5.02 (m, 1H), 5.95-6.06 (m, 1H), 7.35 (dd, J=4.0, 8.4 Hz, 1H),7.50 (d, J=9.2 Hz, 1H), 8.01 (d, J=9.2 Hz, 1H), 8.21-8.27 (m, 1H), 8.76(dd, J=1.6, 4.0 Hz, 1H).

(2) 5-[2-(1,4-Dioxa-8-azaspiro[4.5]decan-8-yl)ethyl]-6-methoxyquinoline

1.24 g of 5-allyl-6-methoxyquinoline was dissolved in 5 ml of t-butanol.Thereafter, 70 ml of a t-butanol-water (1:1) solution containing 10.3 gof AD-mix-α was added to the reaction solution, and the obtained mixturewas then stirred at room temperature overnight. Thereafter, 15 g ofsodium sulfite was added to the reaction solution, and the obtainedmixture was then stirred at room temperature for 30 minutes whilecooling on ice. A saturated sodium chloride aqueous solution was addedto the reaction solution, followed by extraction with methylenechloride. The extract was dried over magnesium sulfate and thenconcentrated under a reduced pressure, so as to obtain 1.69 g of3-(6-methoxyquinolin-5-yl)propane-1,2-diol. This compound was used inthe following reaction without further purification.

0.81 g of 3-(6-methoxyquinolin-5-yl)propane-1,2-diol was dissolved in 24ml of tetrahydrofuran and 8 ml of methanol. Then, 12 ml of watercontaining 1.49 g of sodium metaperiodate was added to the reactionsolution while cooling on ice, and the obtained mixture was then stirredat room temperature for 45 minutes. Thereafter, a saturated sodiumchloride aqueous solution was added to the reaction solution, followedby extraction with methylene chloride. The extract was dried overmagnesium sulfate and then concentrated under a reduced pressure, so asto obtain 0.72 g of (6-methoxyquinolin-5-yl)acetaldehyde. This compoundwas directly used in the following reaction without furtherpurification.

0.72 g of (6-methoxyquinolin-5-yl)acetaldehyde and 0.75 g of1,4-dioxa-8-azaspiro[4.5]decane were dissolved in 30 ml of methylenechloride. Then, 0.50 ml of acetic acid and 0.89 g of sodiumtriacetoxyborohydride were added to the reaction solution, and theobtained mixture was then stirred at room temperature overnight.Thereafter, a saturated sodium bicarbonate aqueous solution was added tothe reaction solution, followed by extraction with methylene chloride.The extract was dried over magnesium sulfate and then concentrated undera reduced pressure. The residue was purified by NH silica gel columnchromatography (hexane-ethyl acetate), so as to obtain 1.01 g of thesubject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.77-1.87 (m, 4H), 2.53-2.77 (m, 6H), 3.23-3.32(m, 2H), 3.97 (s, 3H), 3.98 (s, 4H), 7.37 (dd, J=4.0, 8.4 Hz, 1H), 7.47(d, J=8.8 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 8.26-8.34 (m, 1H), 8.76 (dd,J=1.6, 4.0 Hz, 1H).

(3)1-{1-[2-(1-Acetyl-6-methoxy-1,2,3,4-tetrahydroquinolin-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from5-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxyquinolineaccording to the methods described in Example 52, (2) and (3).

¹H-NMR (DMSO-d₆) δ (ppm): 1.80-1.92 (m, 2H), 1.93-2.14 (m, 4H),2.24-2.33 (m, 2H), 2.38-2.46 (m, 2H), 2.55-2.73 (m, 2H), 2.77-2.85 (m,2H), 3.08-3.16 (m, 2H), 3.63 (t, J=6.4 Hz, 2H), 3.80 (s, 3H), 4.37-4.47(m, 1H), 6.51 (d, J=3.2 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 7.06-7.26 (m,2H), 7.54-7.61 (m, 2H), 7.67 (d, J=3.2 Hz, 1H), 7.91 (br.s, 1H), 8.13(s, 1H).

EXAMPLE 55 Synthesis of1-{1-[2-(6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from5-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxyquinolineaccording to the methods described in Example 53, (1) and (2).

¹H-NMR (DMSO-d₆) δ (ppm): 1.87-2.10 (m, 6H), 2.23-2.32 (m, 2H),2.35-2.42 (m, 2H), 2.66-2.78 (m, 4H), 2.75 (s, 3H), 3.00-3.06 (m, 2H),3.07-3.16 (m, 2H), 3.69 (s, 3H), 4.36-4.47 (m, 1H), 6.46 (d, J=8.8 Hz,1H), 6.51 (d, J=3.2 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 7.21 (br.s, 1H),7.54-7.61 (m, 2H), 7.68 (d, J=3.2 Hz, 1H), 7.91 (br.s, 1H), 8.12 (s,1H).

EXAMPLE 56 Synthesis of1-{1-[2-(6-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) (4-Allyl-5-methoxy-2-nitrobenzyloxy)-t-butyldimethylsilane

229 mg of 4-allyl-5-methoxy-2-nitrobenzyl alcohol was dissolved in 5 mlof N,N-dimethylformamide. Thereafter, 0.17 g of imidazole and 0.23 g oft-butyldimethylsilyl chloride were added to the reaction solution whilecooling on ice. The obtained mixture was stirred at room temperature for2 hours. Thereafter, 34 mg of imidazole and 46 mg oft-butyldimethylsilyl chloride were further added to the reactionsolution. The obtained mixture was stirred at room temperatureovernight. The reaction solution was diluted with ethyl acetate and thenwashed with a saturated ammonium chloride aqueous solution and asaturated sodium chloride aqueous solution. The organic layer was driedover magnesium sulfate and then concentrated under a reduced pressure.The residue was purified by silica gel column chromatography(hexane-ethyl acetate), so as to obtain 330 mg of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 0.15 (s, 6H), 0.98 (s, 9H), 3.37-3.41 (m, 2H),3.93 (s, 3H), 5.05-5.14. (m, 2H), 5.12 (s, 2H), 5.89-6.01 (m, 1H), 7.42(s, 1H), 8.01 (s, 1H).

(2)t-Butyl[4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-5-methoxy-2-nitrobenzyloxy]dimethylsilane

1.37 g of AD-mix-β was dissolved in 10 ml of t-butanol-water (1:1), andthen, 2 ml of a t-butanol solution containing 330 mg of(4-allyl-5-methoxy-2-nitrobenzyloxy)-t-butyldimethylsilane was added tothe reaction solution. The obtained mixture was then stirred at roomtemperature overnight. 1.5 g of sodium sulfite was added to the reactionsolution while cooling on ice, and the obtained mixture was stirred atroom temperature for 1 hour. A saturated sodium chloride aqueoussolution was added to the reaction solution, followed by extraction withmethylene chloride. The extract was dried over magnesium sulfate andthen concentrated under a reduced pressure, so as to obtain 390 mg of3-(4-(t-butyldimethylsilyloxy-methyl)-2-methoxy-5-nitrophenyl)propane-1,2-diol.This compound was directly used in the following reaction withoutfurther purification.

390 mg of3-(4-(t-butyldimethylsilyloxy-methyl)-2-methoxy-5-nitrophenyl)propane-1,2-diolwas dissolved in 8 ml of acetone. Then, 0.33 g of dimethoxypropane and26 mg of pyridinium p-toluenesulfonate were added to the reactionsolution. The obtained mixture was then stirred at room temperature for41 hours. Thereafter, the reaction solution was concentrated under areduced pressure. The residue was diluted with ethyl acetate and thenwashed with water and a saturated sodium chloride aqueous solution. Theorganic layer was dried over magnesium sulfate and then concentratedunder a reduced pressure. The residue was purified by silica gel columnchromatography (hexane-ethyl acetate), so as to obtain 358 mg of thesubject compound.

¹H-NMR (CDCl₃) δ (ppm): 0.15 (s, 6H), 0.99 (s, 9H), 1.34 (s, 3H), 1.43(s, 3H), 2.87 (dd, J=6.0, 13.6 Hz, 1H), 2.96 (dd, J=6.0, 13.6 Hz, 1H),3.64 (dd, J=6.8, 8.0 Hz, 1H), 3.92 (s, 3H), 3.99 (dd, J=5.6, 8.0 Hz,1H), 4.33-4.41 (m, 1H), 5.12 (s, 2H), 7.43 (s, 1H), 8.08 (s, 1H).

(3)4-[(2,2-Dimethyl-[1,3]dioxolan-4-yl)methyl]-5-methoxy-2-nitrobenzaldehyde

358 mgof-t-butyl(4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-5-methoxy-2-nitrobenzyloxy)dimethylsilanewas dissolved in 10 ml of tetrahydrofuran. While cooling on-ice, 1 ml ofa tetrahydrofuran solution containing 1.0 M tetrabutyl ammonium fluoridewas added to the reaction solution, and the obtained mixture was thenstirred at room temperature for 3 hours. Thereafter, the reactionsolution was diluted with ethyl acetate and then washed with a saturatedsodium chloride aqueous solution. The organic layer was dried overmagnesium sulfate and then concentrated under a reduced pressure. Theresidue was purified by silica gel column chromatography (hexane-ethylacetate), so as to obtain 253 mg of(4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-5-methoxy-2-nitrophenyl)methanol.

Thereafter, 253 mg of(4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-5-methoxy-2-nitrophenyl)methanolwas dissolved in 10 ml of methylene chloride. Then, 2.5 g of activatedmanganese dioxide was added to the reaction solution, and the obtainedmixture was then stirred at room temperature for 66 hours. Thereafter,the reaction solution was filtered through celite, and the filtrate wasconcentrated under a reduced pressure, so as to obtain 137 mg of thesubject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.34 (s, 3H), 1.43 (s, 3H), 2.91-3.03 (m, 2H),3.65 (dd, J=6.0, 8.0 Hz, 1H), 3.98 (s, 3H), 4.06 (dd, J=6.0, 8.0 Hz,1H), 4.34-4.43 (m, 1H), 7.32 (s, 1H), 8.07 (s, 1H), 10.47 (s, 1H).

(4)7-[(2,2-Dimethyl-[1,3]dioxolan-4-yl)methyl]-6-methoxy-1,2,3,4-tetrahydroquinolin-2-one

137 mg of4-((2,2-dimethyl-[1,3]dioxolan-4-yl)methyl)-5-methoxy-2-nitrobenzaldehydewas dissolved in 5 ml of toluene. Thereafter, 204 mg ofethoxycarbonylmethylenetriphenylphospholane was added to the reactionsolution, and the obtained mixture was then heated to reflux for 1 hour.The reaction solution was cooled to a room temperature. Thereafter, thereaction solution was concentrated under a reduced pressure. The residuewas purified by silica gel column chromatography (hexane-ethyl acetate),so as to obtain 168 mg of3-(4-((2,2-dimethyl-[1,3]dioxolan-4-yl)methyl)-5-methoxy-2-nitrophenyl)ethylacrylate.

Thereafter, 168 mg of3-(4-((2,2-dimethyl-(1,3]dioxolan-4-yl)methyl)-5-methoxy-2-nitrophenyl)ethylacrylate was dissolved in 5 ml of ethanol. Then, 30 mg of 10% palladiumcarbon was added to the reaction solution, and the obtained mixture wasthen stirred under hydrogen atmosphere for 4 hours. Palladium carbon wasremoved by filtration, and the filtrate was then concentrated under areduced pressure. The residue was dissolved in 5 ml of ethanol. Thereaction solution was stirred at 50° C. for 17 hours. It was then heatedto reflux for 30 minutes. The reaction solution was cooled to a roomtemperature, and it was then concentrated under a reduced pressure. Theresidue was reprecipitated from diethyl ether-hexane, so as to obtain110 mg of the subject compound.

¹H-NMR (DMSO-d₆) δ (ppm): 1.23 (s, 3H), 1.33 (s, 3H), 2.36-2.43 (m, 2H),2.63-2.77 (m, 2H), 2.80-2.87 (m, 2H), 3.53 (dd, J=6.4, 8.0 Hz, 1H), 3.74(s, 3H), 3.90 (dd, J=5.6, 8.0 Hz, 1H), 4.15-4.23 (m, 1H), 6.68 (s, 1H),6.82 (s, 1H), 9.84 (br.s, 1H).

(5)1-{1-[2-(6-Methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

109 mg of7-((2,2-dimethyl-[1,3]dioxolan-4-yl)methyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-2-onewas dissolved in 4 ml of methanol-tetrahydrofuran (1:1). While coolingon ice, 1 ml of 2 N hydrochloric acid was added to the reactionsolution, and the obtained mixture was then stirred at room temperaturefor 3 hours. Thereafter, the reaction solution was concentrated under areduced pressure, so as to obtain 110 mg of7-(2,3-dihydroxypropyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-2-one. Thiscompound was directly used in the following reaction without furtherpurification.

110 mg of7-(2,3-dihydroxypropyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-2-one wasdissolved in 2 ml of methanol and 1 ml of tetrahydrofuran. Thereafter, 2ml of water containing 0.16 g of sodium metaperiodate was added to thereaction solution while cooling on ice. The obtained mixture was stirredat room temperature for 30 minutes. A saturated sodium chloride aqueoussolution was added to the reaction solution, followed by extraction withmethylene chloride. The extract was dried over magnesium sulfate andthen concentrated under a reduced pressure, so as to obtain 87 mg of(6-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)acetaldehyde. Thiscompound was directly used in the following reaction without furtherpurification.

100 mg of 1-(piperidin-4-yl)-1H-indole-6-carboxamide and 87 mg of(6-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)acetaldehyde weresuspended in 5 ml of methylene chloride. Thereafter, 0.05 ml of aceticacid and 0.13 g of sodium triacetoxyborohydride were added to thereaction solution, and the obtained mixture was stirred at roomtemperature overnight. Thereafter, a saturated sodium bicarbonateaqueous solution was added to the reaction solution, followed byextraction with chloroform. The extract was dried over magnesium sulfateand then concentrated under a reduced pressure. The residue was purifiedby silica gel column chromatography (chloroform-methanol) and by NHsilica gel column chromatography (chloroform-methanol), and thenreprecipitated from ethyl acetate, so as to obtain 18 mg of the subjectcompound.

¹H-NMR (DMSO-d₆) δ (ppm): 1.92-2.10 (m, 4H), 2.20-2.30 (m, 2H), 2.40 (t,J=7.6 Hz, 2H), 2.45-2.55 (m, 2H), 2.65-2.72 (m, 2H), 2.83 (t, J=7.6 Hz,2H), 3.06-3.12 (m, 2H), 3.75 (s, 3H), 4.37-4.47 (m, 1H), 6.50 (d, J=3.2Hz, 1H), 6.69 (s, 1H), 6.81 (s, 1H), 7.21 (br.s, 1H), 7.53-7.61 (m, 2H),7.67 (d, J=3.2 Hz, 1H), 7.91 (br.s, 1H), 8.12 (s, 1H), 9.85 (s, 1H).

EXAMPLE 57 Synthesis of1-{1-[2-(6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1)7-[(2,2-Dimethyl-[1,3]dioxolan-4-yl)methyl]-6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-2-one

300 mg of7-((2,2-dimethyl-[1,3]dioxolan-4-yl)methyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-2-onewas dissolved in 6 ml of N,N-dimethylformamide. While cooling on ice, 49mg of 60% sodium hydride was added to the reaction solution, and theobtained mixture was then stirred at room temperature for 30 minutes.Thereafter, 0.29 g of iodomethane was added to the reaction solutionwhile cooling on ice. The obtained mixture was stirred at roomtemperature for 2 hours. The reaction solution was diluted with ethylacetate and then washed with a saturated ammonium chloride aqueoussolution and a saturated sodium chloride aqueous solution. The organiclayer was dried over magnesium sulfate and then concentrated under areduced pressure. The residue was purified by NH silica gel columnchromatography (hexane-ethyl acetate), so as to obtain 310 mg of thesubject compound.

¹H-NMR (DMSO-d₆) δ (ppm): 1.34 (s, 3H), 1.43 (s, 3H), 2.58-2.66 (m, 2H),2.80-2.89 (m, 3H), 2.94 (dd, J=6.0, 14.0 Hz, 1H), 3.32 (s, 3H), 3.65(dd, J=6.0, 7.6 Hz, 1H), 3.80 (s, 3H), 3.97 (dd, J=5.6, 7.6 Hz, 1H),4.32-4.39 (m, 1H), 6.65 (s, 1H), 6.81 (s, 1H).

(2)1-{1-[2-(6-Methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from7-((2,2-dimethyl-[1,3]dioxolan-4-yl)methyl)-6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-2-oneaccording to the method described in Example 56, (5).

¹H-NMR (DMSO-d₆) δ (ppm): 1.92-2.09 (m, 4H), 2.22-2.32 (m, 2H),2.45-2.60 (m, 4H), 2.72-2.86 (m, 4H), 3.08-3.15 (m, 2H), 3.24 (s, 3H),3.78 (s, 3H), 4.37-4.48 (m, 1H), 6.50 (d, J=3.2 Hz, 1H), 6.88 (s, 1H),6.96 (s, 1H), 7.22 (br.s, 1H), 7.53-7.60 (m, 2H), 7.67 (d, J=3.2 Hz,1H), 7.91 (br.s, 1H), 8.13 (s, 1H).

EXAMPLE 58 Synthesis of1-{1-[2-(6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide

The subject compound was synthesized from7-((2,2-dimethyl-[1,3]dioxolan-4-yl)methyl)-6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-2-oneaccording to the method described in Example 56, (5).

¹H-NMR (DMSO-d₆) δ (ppm): 1.93-2.10 (m, 4H), 2.22-2.31 (m, 2H),2.47-2.60 (m, 4H), 2.74-2.85 (m, 4H), 2.82 (d, J=4.4 Hz, 3H), 3.08-3.15(m, 2H), 3.24 (s, 3H), 3.78 (3, 3H), 4.36-4.46 (m, 1H), 6.50 (d, J=3.2Hz, 1H), 6.88 (s, 1H), 6.96 (s, 1H), 7.51-7.58 (m, 2H), 7.67 (d, J=3.2Hz, 1H), 8.05 (s, 1H), 8.30-8.37 (m, 1H).

EXAMPLE 59 Synthesis of1-{1-[2-(1-ethyl-6-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from7-((2,2-dimethyl-[1,3]dioxolan-4-yl)methyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-2-oneaccording to the method described in Example 57.

¹H-NMR (DMSO-d₆) δ (ppm): 1.13 (t, J=7.2, 3H), 1.94-2.07 (m, 4H),2.21-2.30 (m, 2H), 2.46-2.59 (m, 4H), 2.74-2.83 (m, 4H), 3.08-3.16 (m,2H), 3.78 (s, 3H), 3.99 (q, J=7.2 Hz, 2H), 4.37-4.47 (m, 1H), 6.50 (d,J=3.2 Hz, 1H), 6.86 (s, 1H), 7.00 (s, 1H), 7.21 (br.s, 1H), 7.54-7.60(m, 2H), 7.65 (d, J=3.2 Hz, 1H), 7.91 (br.s, 1H), 8.12 (s, 1H).

EXAMPLE 60 Synthesis of1-{1-[2-(3-ethyl-6-methoxy-2-oxo-2,3-dihydrobenzoxazol-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) 3-Ethyl-6-methoxy-5-(3-methyl-2-butenyl)-3H-benzoxazol-2-one

231 mg of 6-methoxy-2-methyl-5-(3-methyl-2-butenyl)benzoxazole wasdissolved in 5 ml of tetrahydrofuran under nitrogen atmosphere.Thereafter, 0.4 ml of a tetrahydrofuran solution containing 0.12 g ofsodium borohydride and 0.1 ml of acetic acid was added to the reactionsolution over 20 minutes, and the obtained mixture was stirred at roomtemperature overnight. The reaction solution was concentrated under areduced pressure. A saturated ammonium chloride aqueous solution wasadded to the residue, followed by extraction with methylene chloride.The extract was washed with a saturated sodium chloride aqueoussolution. The organic layer was dried over magnesium sulfate and thenconcentrated under a reduced pressure. The residue was purified bysilica gel column chromatography (hexane-ethyl acetate), so as to obtain80 mg of 2-ethylamino-5-methoxy-4-(3-methyl-2-butenyl)phenol containinga product whose structure was unknown. This compound was directly usedin the following reaction without further purification.

80 mg of 2-ethylamino-5-methoxy-4-(3-methyl-2-butenyl)phenol wasdissolved in 5 ml of tetrahydrofuran under nitrogen atmosphere. Then,0.11 g of 1,1′-carbonyldiimidazole was added to the reaction solution,and the obtained mixture was then stirred at room temperature for 1hour. Thereafter, the mixture was further stirred at 50° C. for 1 hour.The reaction solution was concentrated under a reduced pressure. Theresidue was diluted with ethyl acetate and then washed with a saturatedsodium chloride aqueous solution. The organic layer was dried overmagnesium sulfate and then concentrated under a reduced pressure. Theresidue was purified by silica gel column chromatography (hexane-ethylacetate), so as to obtain 60 mg of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.35 (t, J=6.8 Hz, 3H), 1.72 (s, 3H), 1.75 (s,3H), 3.33 (d, J=7.2 Hz, 2H), 3.82 (s, 3H), 3.84 (q, J=6.8 Hz, 2H),5.23-5.29 (m, 1H), 6.73 (s, 1H), 6.80 (s, 1H).

(2)1-{1-[2-(3-Ethyl-6-methoxy-2-oxo-2,3-dihydrobenzoxazol-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

The subject compound was synthesized from3-ethyl-6-methoxy-5-(3-methyl-2-butenyl)-3H-benzoxazol-2-one accordingto the method described in Example 4, (4).

¹H-NMR (DMSO-d₆) δ (ppm): 1.26 (t, J=7.2, 3H), 1.93-2.08 (m, 4H),2.24-2.32 (m, 2H), 2.50-2.60 (m, 2H), 2.77-2.84 (m, 2H), 3.08-3.15 (m,2H), 3.80 (s, 3H), 3.82 (q, J=7.2 Hz, 2H), 4.37-4.47 (m, 1H), 6.50 (d,J=3.2 Hz, 1H), 7.14 (s, 1H), 7.17-7.24 (m, 1H), 7.20 (s, 1H), 7.54-7.60(m, 2H), 7.66 (d, J=3.2 Hz, 1H), 7.91 (br.s, 1H), 8.13 (s, 1H).

EXAMPLE 61 Synthesis of1-{1-[2-(7-methoxy-3-methyl-2-oxo-3,4-dihydro-1,3-benzoxazin-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) 2-Allyloxy-4-hydroxybenzaldehyde

15.23 g of 2,4-dihydroxybenzaldehyde was dissolved in 200 ml of methylethyl ketone. Then, 15.54 g of potassium carbonate, 9.73 ml of allylbromide, 18.67 g of potassium iodide, and 3.55 g of tetrabutylammoniumbromide were successively added to the reaction solution. This reactionsolution was heated to reflux under nitrogen atmosphere for 1.5 hours.The precipitate was removed by filtration, and the filtrate wasconcentrated under a reduced pressure. Ethyl acetate and water wereadded to the residue, so as to separate an organic layer. The organiclayer was washed with a saturated sodium chloride solution and thendried over anhydrous magnesium sulfate. After removing the drying agentby filtration, the organic layer was concentrated under a reducedpressure. The residue was then purified by silica gel columnchromatography (hexane/ethyl acetate), so as to obtain 13.72 g of thesubject compound.

¹H-NMR (CDCl₃) δ (ppm): 4.58-4.60 (m, 2H), 5.32-5.36 (m, 1H), 5.40-5.46(m, 1H), 5.99-6.08 (m, 1H), 6.44 (d, J=2.4 Hz, 1H), 6.56 (dd, J=2.4, 8.8Hz, 1H),7.44 (d, J=8.8 Hz, 1H), 9.72 (s, 1H), 11.47 (s, 1H).

(2) 3-Allyl-2,4-dihydroxybenzaldehyde

3.10 g of 2-allyloxy-4-hydroxybenzaldehyde was dissolved in 6 ml ofN,N-dimethylaniline, and the reaction solution was heated to refluxunder nitrogen atmosphere. Approximately 2.5 hours later, the reactionsolution was stood to cool. Thereafter, water and ethyl acetate wereadded to the reaction solution, so as to separate an organic layer. Theobtained organic layer was washed with 5 N hydrochloric acid, water, anda saturated sodium chloride solution, and then dried over anhydrousmagnesium sulfate. After removing the drying agent by filtration, theorganic layer was concentrated under a reduced pressure. The residue wasthen purified by silica gel column chromatography (hexane/ethylacetate), so as to obtain 0.88 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 3.48-3.50 (m, 2H), 5.15-5.23 (m, 2H), 5.87 (s,1H), 5.94-6.04 (m, 1H), 6.50 (d, J=8.4 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H),9.70 (s, 1H), 11.76 (s, 1H).

(3) 8-Allyl-7-hydroxy-3-methyl-3,4-dihydro-2H-1,3-benzoxazin-2-one

0.88 g of 3-allyl-2,4-dihydroxybenzaldehyde was dissolved in 10 ml ofmethanol. 1.92 ml of a methanol solution containing methylamine (40%)was added to the above solution, and the obtained mixture was thenstirred at room temperature for approximately 30 minutes. Thereafter,this reaction solution was cooled on ice, and sodium borohydride wasthen added thereto little at a time. The reaction solution was stirredat room temperature for 15 minutes. Thereafter, the solvent was removedunder a reduced pressure. A saturated sodium bicarbonate aqueoussolution was added to the residue, followed by extraction with ethylacetate twice. The obtained organic layer was washed with a saturatedsodium chloride solution and then dried over anhydrous magnesiumsulfate. After removing the drying agent by filtration, the organiclayer was concentrated under a reduced pressure. 2.40 g of1,1′-carbonyldiimidazole and 30 ml of anhydrous tetrahydrofuran wereadded to the residue, and the obtained mixture was then heated to refluxfor 2.5 hours. The reaction solution was cooled to a room temperature,and 5 ml of methanol was then added to the reaction solution. Thesolvent was removed under a reduced pressure. The residue was purifiedby silica gel column chromatography (hexane/ethyl acetate), so as toobtain 0.66 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 3.11 (s, 3H), 3.52-3.54 (m, 2H), 4.39 (bs, 2H),5.11-5.18 (m, 2H), 5.24 (s, 1H), 5.92-6.02 (m, 1H), 6.62 (d, J=8.2 Hz,1H), 6.85 (d, J=8.2 Hz, 1H).

(4) 8-Allyl-7-methoxy-3-methyl-3,4-dihydro-2H-1,3-benzoxazin-2-one

0.66 g of 8-allyl-7-hydroxy-3-methyl-3,4-dihydro-2H-1,3-benzoxazin-2-onewas dissolved in 6 ml of N,N-dimethylformamide. 0.63 g of potassiumcarbonate and 0.94 ml of methyl iodide were added to the above solution,and the obtained mixture was then stirred at room temperature overnightunder nitrogen atmosphere. Thereafter, water and ethyl acetate wereadded to the reaction solution, so as to separate an organic layer. Theobtained organic layer was washed with a sodium thiosulfate aqueoussolution, water, and a saturated sodium chloride solution, and thendried over anhydrous magnesium sulfate. After removing the drying agentby filtration, the organic layer was concentrated under a reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate), so as to obtain 0.58 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 3.11 (s, 3H), 3.46-3.48 (m, 2H), 3.83 (s, 3H),4.40 (bs, 2H), 4.94-5.05 (m, 2H), 5.89-5.99 (m, 1H), 6.64 (d, J=8.6 Hz,1H), 6.90 (d, J=8.6 Hz, 1H).

(5)8-(2,3-Dihydroxypropyl)-7-methoxy-3-methyl-3,4-dihydro-2H-1,3-benzoxazin-2-one

12 ml of t-butanol and 10 ml of water were added to and dissolved in0.58 g of8-allyl-7-methoxy-3-methyl-3,4-dihydro-2H-1,3-benzoxazin-2-one. 2.48 gof AD-mix-β was added to this solution, and the obtained mixture wasstirred at room temperature overnight. After confirming thedisappearance of raw material, 2.97 g of sodium sulfite was added to thereaction solution, and the obtained mixture was then stirred forapproximately 45 minutes. Thereafter, water and chloroform were added tothe reaction solution, so as to separate an organic layer. The obtainedorganic layer was washed with a saturated sodium chloride solution andthen dried over anhydrous magnesium sulfate. After removing the dryingagent by filtration, the organic layer was concentrated under a reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/methanol), so as to obtain 0.55 g of the subjectcompound.

¹H-NMR (CDCl₃) δ (ppm): 2.92-3.02 (m, 2H), 3.11 (s, 3H), 3.50 (dd,J=5.8, 12.0 Hz, 1H), 3.60 (dd, J=3.6, 12.0 Hz, 1H), 3.85 (s, 3H),3.92-3.96 (m, 1H), 4.40 (s, 2H), 6.66 (d, J=8.4 Hz, 1H), 6.94 (d, J=8.4Hz, 1H).

(6)1-{1-[2-(7-Methoxy-3-methyl-2-oxo-3,4-dihydro-1,3-benzoxazin-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-caboxamide

114 mg of8-(2,3-dihydroxypropyl)-7-methoxy-3-methyl-3,4-dihydro-2H-1,3-benzoxazin-2-onewas dissolved in 2 ml of tetrahydrofuran, 2 ml of methanol, and 1.3 mlof water. Thereafter, 182 mg of sodium metaperiodate was added thereto,and the obtained mixture was vigorously stirred. After confirming thedisappearance of materials, water and ethyl acetate were added to thereaction solution, so as to separate an organic layer. The obtainedorganic layer was washed with a saturated sodium chloride solution andthen dried over anhydrous magnesium sulfate. After removing the dryingagent by filtration, the organic layer was concentrated under a reducedpressure, so as to obtain 135 mg of a crude aldehyde form.

135 mg of the aforementioned crude aldehyde form dissolved in 4 ml ofdichloromethane and 40.5 μl of acetic acid were successively added to 86mg of 1-(piperidin-4-yl)-1H-indole-6-carboxamide, and the obtainedmixture was then stirred for 10 minutes. Thereafter, 112 mg of sodiumtriacetoxyborohydride was added to the reaction solution, and theobtained mixture was then stirred at room temperature overnight.Thereafter, a 10% sodium carbonate aqueous solution and chloroform wereadded to the reaction solution, so as to separate an organic layer. Theobtained organic layer was washed with a saturated sodium chloridesolution and then dried over anhydrous magnesium sulfate. After removingthe drying agent by filtration, the organic layer was concentrated undera reduced pressure. The residue was purified by NH silica gel columnchromatography (ethyl acetate/methanol), so as to obtain 124 mg of thesubject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.04-2.40 (m, 4H), 2.28-2.38 (m, 2H), 2.58-2.66(m, 2H), 2.95-2.99 (m, 2H), 3.12 (s, 3H), 3.21-3.28 (m, 2H), 3.84 (s,3H), 4.32-4.40 (m, 2H), 4.40 (s, 2H), 5.56 (bs, 1H), 6.29 (bs, 1H), 6.55(d, J=3.3 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 7.38(d, J=3.3 Hz, 1H), 7.45 (br d, 1H), 7.63 (d, J=8.0 Hz, 1H), 8.08 (br s,1H).

EXAMPLE 62 Synthesis of1-{1-[2-(7-methoxy-3-methyl-2,4-dioxo-3,4-dihydro-2H-1,3-benzoxazin-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-caboxamide

(1) Methyl 4-(allyloxy)-2-hydroxybenzoate

20.05 g of methyl 2,4-dihydroxybenzoate was dissolved in 250 ml ofacetone, and then, 17.31 g of potassium carbonate and 12.4 ml of allylbromide were successively added to the reaction solution. The obtainedmixture was stirred at room temperature under nitrogen atmosphere forapproximately 2.5 days. Thereafter, the precipitate was removed byfiltration, and the filtrate was concentrated under a reduced pressure.The obtained residue was purified by silica gel column chromatography(hexane/ethyl acetate), so as to obtain 20.36. g of the subjectcompound. A peak that was assumed to be an isomer (methyl4-(allyloxy)-2-hydroxybenzoate) was slightly observed in NMR.

¹H-NMR (CDCl₃) δ (ppm): 3.91 (s, 3H), 4.54-4.57 (m, 2H), 5.30-5.33 (m,1H), 5.39-5.45 (m, 1H), 5.99-6.08 (m, 1H), 6.44-6.47 (m, 2H), 7.72-7.75(m, 1H), 10.96 (s, 1H).

(2) Methyl 3-allyl-2,4-dihydroxybenzoate

9.47 g of methyl 4-(allyloxy)-2-hydroxybenzoate was dissolved in 25 mlof N,N-dimethylaniline, and the obtained mixture was then heated toreflux under nitrogen atmosphere. Approximately 2.5 hours later, thereaction mixture was cooled to a room temperature. Thereafter, water andethyl acetate were added to the reaction solution, so as to separate anorganic layer. The obtained organic layer was washed with 5 Nhydrochloric acid, water, and a saturated sodium chloride solution, andthen dried over anhydrous magnesium sulfate. After removing the dryingagent by filtration, the organic layer was concentrated under a reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate), so as to obtain 2.30 g of thesubject compound. A peak that was assumed to be an isomer (methyl5-(allyloxy)-2,4-dihydroxybenzoate) was slightly observed in NMR.

¹H-NMR (CDCl₃) δ (ppm): 3.48-3.50 (m, 2H), 3.91 (s, 3H), 5.11-5.18 (m,2H), 5.56 (s, 1H), 6.38 (d, J=8.8 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 11.27(s, 1H).

(3) Methyl 3-allyl-2-hydroxy-4-methoxybenzoate

2.30 g of methyl 3-allyl-2,4-dihydroxybenzoate was dissolved in 30 ml ofacetone, and then, 1.83 g of potassium carbonate and 0.76 ml of methyliodide were added to the above solution. The obtained mixture was thenstirred at room temperature under nitrogen atmosphere overnight.Thereafter, a 5% sodium hydrogen sulfate aqueous solution, water, andethyl acetate were added to the reaction solution, so as to separate anorganic layer. The obtained organic layer was washed with a sodiumthiosulfate aqueous solution, water, and a saturated sodium chloridesolution, and then dried over anhydrous magnesium sulfate. Afterremoving the drying agent by filtration, the organic layer wasconcentrated under a reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane/ethyl acetate), so as toobtain 1.83 g of the subject compound. A peak that was assumed to be anisomer (methyl 5-(allyloxy)-2-hydroxy-4-methoxybenzoate) was slightlyobserved in NMR.

¹H-NMR (CDCl₃) δ (ppm): 3.41-3.43 (m, 2H), 3.86 (s, 3H), 3.91 (s, 3H),4.93-5.02 (m, 2H), 5.90-6.00 (m, 1H), 6.45 (d, J=8.8 Hz, 1H), 7.73 (d,J=8.8 Hz, 1H), 11.05 (s, 1H).

(4) Methyl 3-allyl-4-methoxy-2-(methoxymethoxy)benzoate

Sodium hydride (60%) was washed with n-hexane and then suspended in 2 mlof anhydrous tetrahydrofuran. This suspension was cooled on ice and thenstirred under nitrogen atmosphere. 2.30 g of methyl3-allyl-2-hydroxy-4-methoxybenzoate dissolved in 8 ml of anhydroustetrahydrofuran was added to the above suspension. The reaction solutionwas stirred at room temperature for approximately 1 hour. Thereafter,1.25 ml of chloromethyl methyl ether was added to the reaction solution,and the obtained mixture was further stirred overnight. Thereafter, a10% sodium carbonate aqueous solution and ethyl acetate were added tothe reaction solution, so as to separate an organic layer. The obtainedorganic layer was washed with a saturated sodium chloride solution andthen dried over anhydrous magnesium sulfate. After removing the dryingagent by filtration, the organic layer was concentrated under a reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate), so as to obtain 1.32 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 3.49-3.51 (m, 2H), 3.58 (s, 3H), 3.86 (s, 6H),4.94-5.00 (m, 2H), 5.04 (s, 2H), 5.90-6.00 (m, 1H), 6.68 (d, J=8.8 Hz,1H), 7.79 (d, J=8.8 Hz, 1H).

(5) 3-Allyl-4-methoxy-2-(methoxymethoxy)benzoic acid

1.32 g of methyl 3-allyl-4-methoxy-2-(methoxymethoxy)benzoate wasdissolved in 12 ml of methanol, and the obtained mixture was thenstirred while cooling on ice. Thereafter, 2.97 ml of a 5 N sodiumhydroxide aqueous solution was added to the reaction mixture, and theobtained mixture was then stirred at room temperature overnight. Thereaction solution was cooled on ice, and ethyl acetate was addedthereto. Then, the obtained mixture was adjusted to be approximately pH5 with addition of a 5% sodium hydrogen sulfate aqueous solution. Anorganic layer was separated, and a water layer was extracted with ethylacetate. The obtained organic layers were gathered. The combined organiclayer was washed with water and a saturated sodium chloride solution,and then dried over anhydrous magnesium sulfate. After removing thedrying agent by filtration, the organic layer was concentrated under areduced pressure, so as to obtain 1.19 g of the subject compound. Thiscompound was used in the following reaction without furtherpurification.

¹H-NMR (CDCl₃)δ(ppm): 3.44-3.46 (m, 2H), 3.59 (s, 3H), 3.89 (s, 3H),4.95-5.03 (m, 2H), 5.13 (s, 2H), 5.92-6.01 (m, 1H), 6.79 (d, J=8.8 Hz,1H), 8.02 (d, J=8.8 Hz, 1H), 10.8 (bs, 1H).

(6) 8-Allyl-7-methoxy-3-methyl-2H-1,3-benzoxazin-2,4(3H)-dione

1.20 g of 3-allyl-4-methoxy-2-(methoxymethoxy)benzoic acid was dissolvedin 15 ml of anhydrous tetrahydrofuran, and 0.84 g of1,1′-carbonyldiimidazole was then added thereto. The obtained mixturewas stirred at room temperature under nitrogen atmosphere for 25minutes. Thereafter, 11.8 ml of methylamine (a 2.0 M tetrahydrofuransolution) was added to the reaction solution, and the obtained mixturewas then stirred at room temperature for approximately 5 hours.Thereafter, the reaction mixture was cooled on ice, and 2.5 ml ofconcentrated hydrochloric acid was added thereto. The obtained mixturewas stirred at room temperature for 15 minutes. The reaction solutionwas extracted with ethyl acetate. The organic layer was washed withwater 3 times and then washed with a saturated sodium bicarbonateaqueous solution and a saturated sodium chloride solution. The resultantproduct was then dried over anhydrous magnesium sulfate. After removingthe drying agent by filtration, the organic layer was concentrated undera reduced pressure. 20 ml of anhydrous tetrahydrofuran was added to theobtained residue, and then, 1.53 g of 1,1′-carbonyldiimidazole was addedthereto. The reaction mixture was heated to reflux under nitrogenatmosphere for approximately 2 hours. The reaction solution was cooledto a room temperature, and the solvent was then removed under a reducedpressure. Ethyl acetate and water were added to the residue, so as toseparate an organic layer. The obtained organic layer was washed withwater twice and then with a saturated sodium chloride solution. Theresultant product was then dried over anhydrous magnesium sulfate. Afterremoving the drying agent by filtration, the organic layer wasconcentrated under a reduced pressure. The residue was reprecipitatedfrom ethyl acetate-n-hexane, so as to obtain 0.97 g of the subjectcompound.

¹H-NMR (CDCl₃) δ (ppm): 3.45 (s, 3H), 3.52-3.54 (m, 2H), 3.94 (s, 3H),4.97-5.06 (m, 2H), 5.85-5.95 (m, 1H), 6.90 (d, J=8.8 Hz, 1H), 7.96 (d,J=8.8 Hz, 1H).

(7) 3-Allyl-2-hydroxy-4-methoxy-N-methylbenzamide

3.94 g of AD-mix-β was added to a mixture consisting of 0.97 g of8-allyl-7-methoxy-3-methyl-2H-1,3-benzoxazin-2,4(3H)-dione, 30 ml oftert-butanol, and 20 ml of water. The obtained mixture was stirred atroom temperature overnight. Thereafter, 4.73 g of sodium sulfite wasadded to the reaction solution, and the obtained mixture was stirred for50 minutes. The reaction solution was adjusted to be approximately pH 5with addition of 1 N hydrochloric acid, and the reaction mixture wasthen extracted with ethyl acetate. The obtained organic layer was washedwith a saturated sodium chloride solution and then dried over anhydrousmagnesium sulfate. After removing the drying agent by filtration, theorganic layer was concentrated under a reduced pressure. 8 ml ofmethanol and 4 ml of tetrahydrofuran were added to the obtained residue,and then, 1.44 ml of a 5 N sodium hydroxide aqueous solution was addedthereto. The reaction mixture was then stirred for 10 minutes. Thereaction solution was cooled on ice, and then 1 N hydrochloric acid wasadded thereto, so as to adjust pH to be approximately 6. Ethyl acetatewas added to the reaction solution for extraction. The obtained organiclayer was washed with a saturated sodium chloride solution and thendried over anhydrous magnesium sulfate. After removing the drying agentby filtration, the organic layer was concentrated under a reducedpressure, so as to obtain 0.81 g of the subject compound. It wasobserved as a mixture of two conformers in NMR. The ratio wasapproximately 2:1. The following measurement results are indicated withthe number of hydrogen atoms such that the sum of conformers becomes asingle molecule.

¹H-NMR (CDCl₃) δ (ppm): 2.99 (s, 2H), 3.02(s, 1H), 3.42-3.44 (m, 2H),3.85 (s, 3H), 4.94-5.04 (m, 2H), 5.93-6.02 (m, 1H), 6.14 (br s, 1H),6.41 (d, J=8.8 Hz, 1H), 7.21 (d, J=8.8 Hz, 0.33H), 7.21 (d, J=8.8 Hz,0.67H), 12.69 (br s, 1H).

(8) 3-Allyl-2-(benzyloxy)-4-methoxy-N-methylbenzamide

0.15 g of sodium hydride was washed with n-hexane, and it was -thensuspended in 0.5 ml of anhydrous tetrahydrofuran. The suspension wascooled on ice and then stirred under nitrogen atmosphere. Thereafter,0.81 g of 3-allyl-2-hydroxy-4-methoxy-N-methylbenzamide dissolved in 5ml of anhydrous tetrahydrofuran was added to the above suspension. Thereaction mixture was stirred at room temperature for 30 minutes. Thereaction mixture was then cooled on ice, and 520 μl of benzyl bromidewas added thereto. The obtained mixture was stirred at room temperaturefor 40 minutes. Thereafter, 3 ml of N,N-dimethylformamide was added tothe reaction solution, and the obtained mixture was further stirred for1 hour. Ice was added to the reaction mixture, followed by extractionwith ethyl acetate. The organic layer was washed with water 3 times andthen with a saturated sodium chloride solution. Then, the resultantproduct was dried over anhydrous magnesium sulfate. After removing thedrying agent by filtration, the organic layer was concentrated under areduced pressure. The residue was reprecipitated from ethylacetate-n-hexane, so as to obtain 0.49 g of the subject compound. It wasobserved as a mixture of two conformers in NMR. The ratio wasapproximately 1:1. The following measurement results are indicated withthe number of hydrogen atoms such that the sum of conformers becomes asingle molecule.

¹H-NMR (CDCl₃) δ (ppm): 2.84 (s, 1.5H), 2.85 (s, 1.5H), 3.51-3.53 (m,2H), 3.88 (s, 3H), 4.84 (s, 2H), 4.97-5.02 (m, 2H), 5.98-6.07 (m, 1H),6.81 (d, J=8.8 Hz, 1H), 7.38-7.45 (m, 5H), 7.63 (br d, 1H), 8.01 (d,J=8.8 Hz, 1H)

(9) 2-Benzyloxy-3-(2,3-dihydroxypropyl)-4-methoxy-N-methylbenzamide

1.57 g of AD-mix-β was added to a mixture consisting of 0.49 g of3-allyl-2-(benzyloxy)-4-methoxy-N-methylbenzamide, 14 ml oftert-butanol, and 12 ml of water. The obtained mixture was stirred atroom temperature overnight. Thereafter, 1.88 g of sodium sulfite wasadded to the reaction solution, and the obtained mixture was thenstirred at room temperature for 1 hour. The reaction solution wasextracted with ethyl acetate twice. The obtained organic layer waswashed with a saturated sodium chloride solution and then dried overanhydrous magnesium sulfate. After removing the drying agent byfiltration, the organic layer was concentrated under a reduced pressure.The residue was purified by silica gel column chromatography(hexane/ethyl acetate), so as to obtain 0.47 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.90 (d, J=4.8 Hz, 3H), 2.93 (dd, J=6.0, 13.6Hz, 1H), 3.01 (dd, J=3.0, 13.6 Hz, 1H), 3.47 (dd, J=5.2, 11.6 Hz, 1H),3.59 (dd, J=3.6, 11.6 Hz, 1H), 3.91 (s, 3H), 3.94-4.00 (m, 1H), 4.84 (d,J=10.6 Hz, 1H), 4.89 (d, J=10.6 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H),7.39-7.47 (m, 5H), 8.01 (d, J=8.8 Hz, 1H).

(10)1-{1-[2-(2-(benzyloxy)-6-methoxy-3-((methylamine)carbonyl)phenyl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

0.47 g of2-benzyloxy-3-(2,3-dihydroxypropyl)-4-methoxy-N-methylbenzamide wasdissolved in 6 ml of tetrahydrofuran, 6 ml of methanol, and 4 ml ofwater. Thereafter, 0.57 g of sodium metaperiodate was added thereto, andthe obtained mixture was vigorously stirred. After confirming thedisappearance of raw material, water and ethyl acetate were added to thereaction solution, so as to separate an organic layer. A water layer wasextracted with ethyl acetate, and it was gathered with the above organiclayer. The obtained layer was washed with a saturated sodium chloridesolution and then dried over anhydrous magnesium sulfate. After removingthe drying agent by filtration, the organic layer was concentrated undera reduced pressure, so as to obtain 0.49 g of a crude aldehyde form.

0.27 g of 1-(piperidin-4-yl)-1H-indole-6-carboxamide was dissolved in 20ml of dichloromethane. Thereafter, 0.49 g of the aforementioned crudealdehyde form and 129 μl of acetic acid were successively added to theabove reaction solution. The obtained mixture was then stirred for 20minutes. Thereafter, 0.36 g of sodium triacetoxyborohydride was added tothe reaction solution, and the obtained mixture was then stirred at roomtemperature overnight. Thereafter, a 10% sodium carbonate aqueoussolution and chloroform were added to the reaction solution, so as toseparate an organic layer. The obtained organic layer was washed with asaturated sodium chloride solution and then dried over anhydrousmagnesium sulfate. After removing the drying agent by filtration, theorganic layer was concentrated under a reduced pressure. The residue waspurified by NH silica gel column chromatography (ethylacetate/methanol), so as to obtain 0.49 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.04-2.52 (m, 4H), 2.25-2.51 (m, 2H), 2.60-2.64(m, 2H), 2.87 (d, J=4.8 Hz, 3H), 2.97-2.99 (m, 2H), 3.18 (br d, 2H),3.90 (s, 3H), 4.35-4.42 (m, 1H), 4.88 (s, 2H), 5.59 (br s, 1H), 6.15 (brs, 1H), 6.57-6.58 (m, 1H), 6.80 (d, J=8.8 Hz, 1H), 7.30-7.46 (m, 7H),7.56 (br d, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 8.12(s, 1H).

(11)1-{1-[2-(2-Hydroxy-6-methoxy-3-((methylamino)carbonyl)phenyl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

15 ml of methanol and 10 ml of tetrahydrofuran were added to anddissolved in 486 mg of1-(1-(2-(2-(benzyloxy)-6-methoxy-3-((methylamino)carbonyl)phenyl)ethyl)piperidin-4-yl)-1H-indole-6-carboxamide.Thereafter, 74 mg of 10% Pd—C (containing water) was added thereto, andthe obtained mixture was then stirred at room temperature under hydrogenatmosphere overnight. Thereafter, Pd—C was removed by filtration, andthe solvent was removed under a reduced pressure, so as to obtain 408 mgof the subject compound.

¹H-NMR (DMSO-d₆) δ (ppm): 1.94-2.08 (m, 4H), 2.23-2.30 (m, 2H),2.43-2.47 (m, 2H), 2.76-2.80 (m, 5H), 3.12 (br d, 2H), 3.83 (s, 3H),4.38-4.46 (m, 1H), 6.49 (d, J=2.8 Hz, 1H), 6.56 (br d, 1H), 7.20 (s,1H), 7.53-7.58 (m, 2H), 7.66-7.69 (m, 2H), 7.90 (s, 1H), 8.11 (s, 1H),8.17 (br s, 1H).

(12)1-{1-[2-(7-Methoxy-3-methyl-2,4-dioxo-3,4-dihydro-2H-1,3-benzoxazin-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

30 ml of anhydrous tetrahydrofuran was added to 408 mg of1-(1-(2-(2-hydroxy-6-methoxy-3-((methylamino)carbonyl)phenyl)ethyl)piperidin-4-yl)-1H-indole-6-carboxamide.Thereafter, 294 mg of 1,1′-carbonyldiimidazole was added thereto. Theobtained mixture was then heated to reflux under nitrogen atmosphere for5 minutes. Thereafter, 5 ml of N,N-dimethylformamide was added to thereaction solution, and the obtained mixture was then heated to refluxunder nitrogen atmosphere for 45 minutes. The reaction solution wascooled to a room temperature, and the solvent was then removed under areduced pressure. Thereafter, 294 mg of 1,1′-carbonyldiimidazole wasadded to the residue. The reaction mixture was heated to reflux undernitrogen atmosphere for 30 minutes. The reaction solution was cooled toa room temperature, and the solvent was then removed under a reducedpressure. Water was added to the residue, and the precipitate wascollected by filtration. The precipitate was washed with diethyl ether.It was then suspended in ethanol, and the solvent was removed under areduced pressure. Ethyl acetate was added to the residue, followed byfiltration, so as to obtain 451 mg of the subject compound.

¹H-NMR (DMSO-d₆) δ (ppm): 1.94-2.07 (m, 4H), 2.25-2.33 (m, 2H),2.50-2.55 (m, 2H), 2.89-2.92 (m, 2H), 3.14 (br d, 2H), 3.27 (s, 3H),3.96 (s, 3H), 4.39-4.47 (m, 1H), 6.50 (d, J=3.4 Hz, 1H), 7.14 (d, J=8.8Hz, 1H), 7.21 (s, 1H), 7.54-7.60 (m, 2H), 7.66 (d, J=3.4 Hz, 1H), 7.87(d, J=8.8 Hz, 1H), 7.91 (s, 1H), 8.13 (s, 1H).

EXAMPLE 63 Synthesis of1-{1-[2-(2-methoxy-5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) 6-(Allyloxy)-3,4-dihydronaphthalen-1(2H)-one

3.30 ml of allyl bromide was added to a mixture consisting of 5.62 g of6-hydroxy-3,4-dihydroxynaphthalen-1(2H)-one, 5.27 g of potassiumcarbonate, and 60 ml of acetone. The obtained mixture was heated toreflux under nitrogen atmosphere overnight. The reaction solution wascooled to a room temperature, and the precipitate was removed byfiltration. The solvent was removed under a reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate), so as to obtain 6.35 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.08-2.15 (m, 2H), 2.59-2.62 (m, 2H), 2.92 (t,J=6.0 Hz, 2H), 4.58-4.60 (m, 2H), 5.30-5.34 (m, 1H), 5.40-5.45 (m, 1H),6.00-6.10 (m, 1H), 6.72 (d, J=2.6 Hz, 1H), 6.84 (dd, J=2.4, 8.8 Hz, 1H),8.00 (d, J=8.8 Hz, 1H).

(2) 5-Allyl-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one

1.13 g of 6-(allyloxy)-3,4-dihydronaphthalen-1(2H)-one was dissolved in8 ml of N,N-dimethylaniline. The obtained mixture was heated to refluxunder nitrogen atmosphere for 5 hours. In the same manner, 5.21 g of6-(allyloxy)-3,4-dihydronaphthalen-1(2H)-one was dissolved in 40 ml ofN,N-dimethylaniline, and the obtained mixture was heated to reflux undernitrogen atmosphere for 7 hours. The obtained reaction solutions werecooled to a room temperature. The two reaction solutions were mixed, andthen, water and ethyl acetate were added thereto, so as to separate anorganic layer. The obtained organic layer was washed with 5 Nhydrochloric acid, water, and a saturated sodium chloride solution, andthen dried over anhydrous magnesium sulfate. After removing the dryingagent by filtration, the organic layer was concentrated under a reducedpressure. Ethyl acetate and t-butylmethyl ether were added to theresidue, followed by filtration, so as to obtain 3.52 g of the subjectcompound.

¹H-NMR (CDCl₃) δ (ppm): 2.07-2.14 (m, 2H), 2.57-2.61 (m, 2H), 2.89 (t,J=6.0 Hz, 2H), 3.45-3.47 (m, 2H), 4.97-5.02 (m, 1H), 5.07-5.11 (m, 1H),5.65 (s, 1H), 5.91-6.01 (m, 1H), 6.78 (d, J=8.8 Hz, 1H), 7.95 (d, J=8.8Hz, 1H).

(3) 5-Allyl-6-methoxy-3,4-dihydronaphthalen-1(2H)-one

901 μl of methyl iodide was added to a mixture consisting of 1.46 g of5-allyl-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one, 1.20 g of potassiumcarbonate, and 15 ml of N,N-dimethylformamide. The obtained mixture wasstirred at room temperature under nitrogen atmosphere overnight.Thereafter, water and ethyl acetate were added to the reaction solution,so as to separate an organic layer. The obtained organic layer waswashed with water (5 times) and a saturated sodium chloride solution,and then dried over anhydrous magnesium sulfate. After removing thedrying agent by filtration, the organic layer was concentrated under areduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate), so as to obtain 1.51 g of thesubject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.06-2.13 (m, 2H), 2.57-2.61 (m, 2H), 2.89 (t,J=6.0 Hz, 2H), 3.43-3.46 (m, 2H), 3.88 (s, 3H), 4.87-4.93 (m, 1H),4.97-5.00 (m, 1H), 5.85-5.94 (m, 1H), 6.86 (d, J=8.8 Hz, 1H), 8.03 (d.J=8.8 Hz, 1H).

(4) 5-(2,3-Dihydroxypropyl)-6-methoxy-3,4-dihydronaphthalen-1(2H)-one

6.99 g of AD-mix-β, 15 ml of tert-butanol, and 20 ml of water wereblended. 1.51 g of 5-allyl-6-methoxy-3,4-dihydronaphthalen-1(2H)-one wasdissolved in 14 ml of tert-butanol, and the obtained solution was addedto the above mixture. The obtained mixture was then stirred at roomtemperature overnight. Thereafter, 8.38 g of sodium sulfite was addedthereto, and the obtained mixture was stirred for approximately 1 hour,followed by extraction with ethyl acetate. The obtained organic layerwas washed with a saturated sodium chloride solution and then dried overanhydrous magnesium sulfate. After removing the drying agent byfiltration, the organic layer was concentrated under a reduced pressure.Ethyl acetate and hexane were added to the residue, followed byfiltration, so as to obtain 1.51 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.09-2.15 (m, 2H), 2.59-2.62 (m, 2H), 2.91-3.05(m, 4H), 3.-52 (dd, J=6.0, 11.2 Hz, 1H), 3.66 (dd, J=3.4, 11.2 Hz, 1H),3.89-3.97 (m, 1H), 3.92 (s, 3H), 6.88 (d, J=8.8 Hz, 1H), 8.06 (d, J=8.8Hz, 1H).

(5)1-{1-[2-(2-Methoxy-5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

0.13 g of5-(2,3-dihydroxypropyl)-6-methoxy-3,4-dihydronaphthalen-1(2H)-one wasdissolved in a mixed solution consisting of 2 ml of tetrahydrofuran, 2ml of methanol and 1.3 ml of water. Thereafter, 224 mg of sodiummetaperiodate was added-thereto, and the obtained mixture was vigorouslystirred for 30 minutes. After confirming the disappearance of the rawmaterial, water and ethyl acetate were added to the reaction solution,so as to separate an organic layer. A water layer was extracted withethyl acetate, and the obtained water layer was mixed with theaforementioned organic layer. The obtained layer was washed with asaturated sodium chloride solution and then dried over anhydrousmagnesium sulfate. After removing the drying agent by filtration, theorganic layer was concentrated under a reduced pressure, so as to obtain129 mg of a crude aldehyde form.

105 mg of 1-(piperidin-4-yl)-1H-indole-6-carboxamide was dissolved in 4ml of dichloromethane. Thereafter, 129 mg of the aforementioned crudealdehyde form and 49.4 μl of acetic acid were successively added to thereaction solution, and the obtained mixture was then stirred for 15minutes. Thereafter, 137 mg of sodium triacetoxyborohydride was added tothe reaction solution, and the obtained mixture was then stirred at roomtemperature overnight. Thereafter, a 10% sodium carbonate aqueoussolution and chloroform were added to the reaction solution, so as toseparate an organic layer. The obtained organic layer was washed with asaturated sodium chloride solution and then dried over anhydrousmagnesium sulfate, followed by filtration. The organic layer wasconcentrated under a reduced pressure and dried. Ethyl acetate andtert-butylmethyl ether were added to the residue, followed byfiltration, so as to obtain 142 mg of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 2.05-2.16 (m, 6H), 2.32 (br s, 2H), 2.50-2.55(m, 2H), 2.60-2.63 (m, 2H), 2.92-2.98 (m, 4H), 2.25 (br d, 2H), 3.91 (s,3H), 4.38-4.45 (m, 1H), 5.62 (br s, 1H), 6.17 (br s, 1H), 6.58-6.59 (m,1H), 6.86 (d, J=8.8 Hz, 1H), 7.39-7.43 (m, 2H), 7.65 (d, J=8.0 Hz, 1H),8.04 (d, J=8.8 Hz, 1H), 8.13 (s, 1H).

EXAMPLE 64 Synthesis of1-{1-[2-(2-methoxy-6,6-dimethyl-5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

(1) 6-Methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one

A mixture consisting of 7.12 g of potassium tert-butoxide, 20 ml oftert-butanol, and 50 ml of toluene was cooled on ice and then stirredunder nitrogen atmosphere. 5.02 g of6-hydroxy-2,2-dimethyl-3,4-dinaphthalen-1(2H)-one dissolved in 100 ml oftoluene was added to the above mixture. Ten minutes later, 3.99 ml ofmethyl iodide was added to the reaction solution, and the obtainedmixture was stirred at room temperature overnight. Thereafter, water andethyl acetate were added to the reaction solution, so as to separate anorganic layer. The obtained organic layer was successively washed withwater (5 times), a 10% sodium carbonate aqueous solution, and asaturated sodium chloride solution. The resultant product was then driedover anhydrous sodium sulfate. After removing the drying agent byfiltration, the organic layer was concentrated under a reduced pressure.The residue was purified by silica gel column chromatography(hexane/ethyl acetate), so as to obtain 3.69 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.21 (s, 6H), 1.96 (t, J=6.4 Hz, 2H), 2.95 (d,J=6.4 Hz, 2H), 3.85 (s, 3H), 6.66-6.67 (m, 1H), 6.83 (dd, J=2.8, 8.8 Hz,1H), 8.02 (d, J=8.8 Hz, 1H).

(2) 6-Hydroxy-3,4-dihydronaphthalen-1(2H)-one

3.69 g of 6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one wasdissolved in 70 ml of anhydrous methylene chloride. The obtainedsolution was cooled in a dry ice-acetone bath. Thereafter, 36 ml ofboron tribromide (a 1.0 M methylene chloride solution) was addedthereto, and the obtained mixture was stirred at room temperatureovernight. Thereafter, the reaction solution was again cooled in a dryice-acetone bath. 36 ml of boron tribromide (a 1.0 M methylene chloridesolution) was added thereto, and the obtained mixture was stirred atroom temperature overnight. Thereafter, the reaction solution was pouredinto ice, and chloroform was then added thereto. An insolubleprecipitate was removed by filtration. The organic layer was separatedand then dried over anhydrous sodium sulfate. The obtained solution waspassed through a glass filter filled with silica gel, and the solventwas removed under a reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate), so as to obtain 1.52 gof the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.20 (s, 6H), 1.94-1.97 (m, 2H), 2.92 (t, J=6.4Hz, 2H), 5.57 (s, 1H), 6.62-6.63 (m, 1H), 6.74 (dd. J=2.8, 8.4 Hz, 1H),7.97 (d, J=8.4 Hz, 1H).

(3) 6-(Allyloxy)-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one

830 μl of allyl bromide was added to a mixture consisting of 1.52 g of6-hydroxy-3,4-dihydronaphthalen-1(2H)-one, 1.22 g of potassiumcarbonate, and 15 ml of N,N-dimethylformamide. The obtained mixture wasstirred at room temperature under nitrogen atmosphere overnight. Waterand ethyl acetate were added to the reaction solution, so as to obtainan organic layer. The obtained organic layer was successively washedwith water (4 times) and a saturated sodium chloride solution, and thendried over anhydrous sodium sulfate. After removing the drying agent byfiltration, the organic layer was concentrated under a reduced pressure.The residue was purified by silica gel column chromatography(hexane/ethyl acetate), so as to obtain 1.69 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.20 (s, 6H), 1.96 (t, J=6.4 Hz, 2H), 2.94 (t,J=6.4 Hz, 2H), 4.58-4.60 (m, 2H), 5.30-5.33 (m, 1H), 5.40-5.45 (m, 1H),6.00-6.10 (m, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.84 (dd, J=2.4, 8.4 Hz, 1H),8.01 (d, J=8.4 Hz, 1H).

(4) 5-Allyl-6-hydroxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one

1.69 g of 6-(allyloxy)-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one wasdissolved in 10 ml of N,N-dimethylaniline, and the obtained mixture washeated to reflux under nitrogen atmosphere for 7 hours. The reactionsolution was cooled to a room temperature. Water and ethyl acetate wereadded to the reaction solution, so as to obtain an organic layer. Theobtained organic layer was successively washed with 5 N hydrochloricacid (3 times), water (4 times), and a saturated sodium chloridesolution. The resultant product was then dried over anhydrous sodiumsulfate. After removing the drying agent by filtration, the organiclayer was concentrated under a reduced pressure. Hexane was added to theresidue, and the precipitate was then collected by filtration, so as toobtain 1.06 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.19 (s, 6H), 1.95 (t, J=6.4 Hz, 2H), 2.89 (t,J=6.4 Hz, 2H), 3.44-3.47 (m, 2H), 4.97-5.03 (m; 1H), 5.07-5.10 (m, 1H),5.92-6.01 (m, 1H), 6.78 (d, J=8.6 Hz, 1H), 7.94 (d, J=8.6 Hz, 1H).

(5) 5-Allyl-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one

575 μl of methyl iodide was added to a mixture consisting of 1.06 g of5-allyl-6-hydroxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one, 0.77 gof potassium carbonate, and 10 ml of N,N-dimethylformamide. The obtainedmixture was stirred at room temperature under nitrogen atmosphereovernight. Water and ethyl acetate were added to the reaction solution,so as to obtain an organic layer. The obtained organic layer was washedwith water (5 times) and a saturated sodium chloride solution, and thendried over anhydrous sodium sulfate. After removing the drying agent byfiltration, the organic layer was concentrated under a reduced pressure.The residue was purified by silica gel column chromatography(hexane/ethyl acetate), so as to obtain 1.09 g of the subject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.19 (s, 6H), 1.94 (t, J=6.4 Hz, 2H), 2.89 (t,J=6.4 Hz, 2H), 3.42-3.45 (m, 2H), 3.88 (s, 3H), 4.87-4.93 (m, 1H),4.96-5.00 (m, 1H), 5.85-5.95 (m, 1H), 6.87 (d, J=9.0 Hz, 1H), 8.03 (d,J=9.0 Hz, 1H).

(6)5-(2,3-Dihydroxypropyl)-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one

4.47 g of AD-mix-β was added to a mixture consisting of 1.09 g of5-allyl-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one, 17 ml oftert-butanol, and 17 ml of water. The obtained mixture was stirred atroom temperature overnight. Thereafter, 5.37 g of sodium sulfite wasadded to the reaction solution, and the obtained mixture was stirred for35 minutes, followed by extraction with ethyl acetate. The obtainedorganic layer was washed with a saturated sodium chloride solution andthen dried over anhydrous sodium sulfate. After removing the dryingagent by filtration, the reaction solution was concentrated under areduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/methanol), so as to obtain 1.25 g of thesubject compound.

¹H-NMR (CDCl₃) δ (ppm): 1.19 (s, 3H), 1.19 (s, 3H), 1.97 (t, J=6.7 Hz,2H), 2.14 (br s, 1H), 2.37 (br s, 1H), 2.90-3.05 (m, 4H), 3.51-3.55 (m,1H), 3.65-3.69 (m, 1H), 3.89-3.96 (m, 1H), 3.91 (s, 3H), 6.89 (d, J=8.8Hz, 1H), 8.05 (d, J=8.8 Hz, 1H).

(7)1-{1-[2-(2-Methoxy-6,6-dimethyl-5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide

0.13 g of5-(2,3-dihydroxypropyl)-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-onewas dissolved in a mixed solution consisting of 2 ml of tetrahydrofuran,2 ml of methanol, and 1.3 ml of water. Thereafter, 197 mg of sodiummetaperiodate was added thereto, and the obtained mixture was vigorouslystirred for 30 minutes. After confirming the disappearance of the rawmaterial, water and ethyl acetate were added to the reaction solution,so as to separate an organic layer. A water layer was extracted withethyl acetate, and the obtained water layer was mixed with theaforementioned organic layer. The obtained layer was washed with asaturated sodium chloride solution and then dried over anhydrousmagnesium sulfate. After removing the drying agent by filtration, theorganic layer was concentrated under a reduced pressure, so as to obtain117 mg of a crude aldehyde form.

93 mg of 1-(piperidin-4-yl)-1H-indole-6-carboxamide was dissolved in 4ml of dichloromethane. Thereafter, 117 mg of the aforementioned crudealdehyde form and 43.8 μl of acetic acid were successively added to thereaction solution, and the obtained mixture was then stirred for 10minutes. Thereafter, 122 mg of sodium triacetoxyborohydride was added tothe reaction solution, and the obtained mixture was then stirred at roomtemperature for 50 minutes. Thereafter, a 10% sodium carbonate aqueoussolution and chloroform were added to the reaction solution, so as toseparate an organic layer. The obtained organic layer was washed with asaturated sodium chloride solution and then dried over anhydrousmagnesium sulfate. After removing the drying agent by filtration, theorganic layer was concentrated under a reduced pressure. Ethyl acetateand tert-butylmethyl ether were added to the residue, followed byfiltration, so as to obtain 153 mg of the subject compound.

¹H-NMR (DMSO-d₆) δ (ppm): 1.11 (s, 6H), 1.92-2.08 (m, 6H), 2.29-2.33 (m,2H), 2043-2.47 (m, 2H), 2.83-2.87 (m, 2H), 2.94-2.97 (m, 2H), 3.14 (brd, 2H), 3.88 (s, 3H), 4.39-4.47 (m, 1H), 6.51 (d, J=2.8 Hz, 1H), 7.03(d, J=8.8 Hz, 1H), 7.22 (s, 1H), 7.55-7.61 (m, 2H), 7.67 (d, J=3.6 Hz,1H), 7.84 (d, J=8.8 Hz, 1H), 7.92 (s, 1H), 8.13 (s, 1H).

EXAMPLE 65 Synthesis of{1-[1-(3,4-dihydro-7-methoxy-1(2H)-naphthalenon-8-yl)ethylpiperidin-4-yl]-(1H)-indole-6-yl}carboxamide

(1) 3,4-Dihydro-7-methoxy-8-(2-propenyl)-1(2H)-naphthalenone

160 mg of 3,4-dihydro-7-hydroxy-8-(2-propenyl)-1(2H)-naphthalenone (CASNo. 122076-30-6), 140 mg of iodomethane, and 400 mg of potassiumcarbonate were dissolved in 15 ml of acetone. The reaction solution wasthen stirred at 70° C. for 1.5 hours. The mixture was filtered and thenwashed with acetone. The organic layer was then concentrated under areduced pressure. The residue was purified by silica gel columnchromatography, so that 140 mg of the subject compound was obtained froman ethyl acetate-hexane eluate (1:10).

¹H-NMR (CDCl₃) δ (ppm) 2.05 (ddd, J=6.0, 6.4, 7.2 Hz, 2H), 2.63 (dd,J=6.4, 7.2 Hz, 2H), 2.88 (dd, J=6.0, 6.4 Hz, 2H), 3.83 (s, 3H),3.85-3.88 (m, 2H), 4.91-5.05 (m, 2H), 5.97-6.08 (m, 1H), 7.01 (d, J=8.4Hz, 1H), 7.10 (d, J=8.4 Hz, 1H).

(2){1-[1-(3,4-Dihydro-7-methoxy-1(2H)-naphthalenon-8-yl)ethylpiperidin-4-yl]-(1H)-indole-6-yl}carboxamide

130 mg of 3,4-dihydro-7-methoxy-8-(2-propenyl)-1(2H)-naphthalenone wasdissolved in 6 ml of tetrahydrofuran and 3 ml of water. Then, 0.2 ml ofa 3.3% osmium tetroxide aqueous solution was added thereto at roomtemperature, and the obtained mixture was then stirred for 15 minutes.Thereafter, 600 mg of sodium perchlorate was added thereto, and theobtained mixture was then stirred at room temperature for 4 hours. Themixture was divided into ethyl acetate and water, and the ethyl acetatelayer was separated. The ethyl acetate layer was washed with a 5% sodiumthiosulfate solution, water, and a saturated sodium chloride solution.The resultant product was then dried over magnesium sulfate. The mixturewas filtered, and the organic layer was concentrated under a reducedpressure. The residue was passed through a silica gel short column, soas to obtain 110 mg of the corresponding crude aldehyde product.

A mixture consisting of 110 mg of the obtained aldehyde, 90 mg of1-(piperidin-4-yl-1H-indole-6-yl)carboxamide, and 100 mg of acetic acid,was dissolved in 5 ml of tetrahydrofuran, and the obtained mixture wasthen stirred at room temperature for 15 minutes. Thereafter, 200 mg ofsodium triacetoxyborohydride was added to the reaction solution, and theobtained mixture was then stirred for 1.5 hours. Thereafter, a 10%potassium carbonate solution was added to the reaction solution,followed by extraction with ethyl acetate. The ethyl acetate layer waswashed with a saturated sodium chloride solution and then dried overmagnesium sulfate, followed by filtration. The layer was thenconcentrated under a reduced pressure. The residue was purified bysilica gel flash chromatography, so that 38 mg of the subject compoundwas obtained in the form of a light yellow solid from a methylenechloride-methanol (10:1) eluate.

¹H-NMR (CDCl₃) δ (ppm) 2.10-2.26 (m, 6H), 2.41-2.57 (m, 2H), 2.63 (dd,J=6.4, 7.2 Hz, 2H), 2.62-2.78 (m, 2H), 2.85 (dd, J=6.0, 6.4 Hz, 2H),3.28-3.44 (m, 4H), 3.83 (s, 3H), 4.36-4.46 (m, 1H), 6.57 (d, J=3.6 Hz,1H), 7.01 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.41 (d, J=3.6 Hz,1H), 7.46 (dd, J=1.2, 8.8 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 8.11 (brs,1H).

EXAMPLE 66 Synthesis of1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamidefumarate

1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide(1.00 g) and fumaric acid (0.249 g) were dissolved in a mixed solventconsisting of acetone (5 ml) and water (15 ml) at 60° C. Thereafter, theobtained mixture was left at room temperature for 1 hour. The depositedsolid was collected by filtration, and the obtained product was thenwashed with a mixed solvent consisting of acetone (2.5 ml) and water(7.5 ml), so as to obtain the subject compound (1.09 g).

¹H-NMR (DMSO-d₆) δ (ppm): 1.40 (s, 6H), 1.94-2.11 (m, 4H), 2.27-2.37 (m,2H), 2.45-2.56 (m, 2H), 2.72 (s, 2H); 2.75-2.84 (m, 5H), 3.12-3.20 (m,2H), 3.87 (s, 3H), 4.38-4.47 (m, 1H), 6.48-6.51 (m, 1H), 6.60 (s, 1.5H),6.75 (d, J=9.6 Hz, 1H), 7.50-7.58 (m, 2H), 7.63-7.67 (m, 2H), 8.05 (brs, 1H), 8.29-8.35 (m, 1H).

EXAMPLE 67 Synthesis of1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamideL-(+)-tartrate

1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide(100 mg) was dissolved in a mixed solvent consisting of tetrahydrofuran(1 ml) and diethyl ether (25 ml). Thereafter, a mixed solvent consistingof tetrahydrofuran (1 ml) and diethyl ether (25 ml) containingL-(+)-tartaric acid (31 mg) was added to the reaction solution at roomtemperature. The deposited solid was collected by filtration, and theobtained product was then washed with diethyl ether, so as to obtain thesubject compound (110 mg).

¹H-NMR (DMSO-d₆) δ (ppm): 1.40 (s, 6H), 1.97-2.14 (m, 4H), 2.40-2.60 (m,4H), 2.72 (s, 2H), 2.78-2.84 (m, 5H), 3.20-3.30 (m, 2H), 3.87 (s, 3H),4.20 (s, 2H), 4.43-4.53 (m, 1H), 6.50 (d, J=3.2 Hz, 1H),6.75 (d, J=8.4Hz, 1H), 7.50-7.58 (m, 2H), 7.63-7.67 (m, 2H), 8.05 (br s, 1H),8.28-8.34 (m, 1H).

EXAMPLE 68 Synthesis of1-(1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamidemaleate

1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide(105 mg) was dissolved in tetrahydrofuran (10 ml). Thereafter, atetrahydrofuran solution (10 ml) containing maleic acid (25 mg)was-added to the reaction solution at room temperature. Thereafter,t-butyl methyl ether was added thereto at room temperature, and theobtained mixture was then concentrated under a reduced pressure. Diethylether was added to the residue for solidification. This suspension wasstirred for 10 minutes while cooling on ice, and a solid was thencollected by filtration. The solid was washed with diethyl ether, so asto obtain the subject compound (117 mg).

¹H-NMR (DMSO-d₆) δ (ppm): 1.44 (s, 6H), 2.17-2.32 (m, 4H), 2.45-2.55 (m,4H), 2.76 (s, 2H), 2.83 (d, J=7.2 Hz, 3H), 2.94-3.05 (m, 2H), 3.25-3.40(m, 2H), 3.91 (s, 3H), 4.74-4.85 (m, 1H), 6.02 (s, 1.5H), 6.54-6.59 (m,1H), 6.82 (d, J=8.0 Hz, 1H), 7.50-7.62 (m, 3H), 7.73 (d, J=8.0 Hz, 1H),8.09 (s, 1H), 8.28-8.35 (m, 1H)

EXAMPLE 69 Synthesis of1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamidefumarate

1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamidefumarate (2.05 g) was dissolved in a mixed solvent consisting ofn-propanol (6 ml) and water (18 ml) at 60° C. Thereafter, the reactionsolution was left at room temperature and then at 0° C. The depositedcrystal was collected by filtration. The collected crystal was dried atroom temperature under a reduced pressure for 30 minutes, so as toobtain the subject compound (2.02 g).

EXAMPLE 70 Synthesis of1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamidefumarate (A-type crystal)

1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide(1.00 g) and fumaric acid (0.249 g) were dissolved in a mixed solventconsisting of acetone (5 ml) and water (15 ml) at 60° C. Thereafter, thereaction solution was left at room temperature for 1 hour. The depositedsolid was collected by filtration. The collected crystal was washed witha mixed solvent consisting of acetone (2.5 ml) and water (7.5 ml), so asto obtain the subject compound (1.09 g).

[X-Ray Powder Diffractometry of A-Type Crystal]

The crystal (Crystal form A) obtained by the above describedcrystallization method was crushed in an agate mortar. The obtainedsample was placed on the platform of X-ray powder diffractometer, andanalysis was carried out under the conditions shown in Table 6 (FIG. 1).

Measurement Conditions TABLE 6 Sample holder Glass or copper TargetCopper Detector Scintillation counter Tube voltage 40 kV Tube current200 mA Slit DSI/2°, RS0.3 mm, SSI/2° Scanning speed 2°/min Samplinginterval 0.02° Scanning range From 5° to 40° Goniometer Verticalgoniometer

EXAMPLE 71 Synthesis of1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide fumarate (B-type crystal)

1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamidefumarate (2.05 g) was dissolved in a mixed solvent consisting ofn-propanol (6 ml) and water (18 ml) at 60° C. Thereafter, the reactionsolution was left at room temperature and then at 0° C. The depositedcrystal was collected by filtration. The collected crystal was dried atroom temperature under a reduced pressure for 30 minutes, so as toobtain the subject compound (2.02 g).

[Powder X-Ray Diffractometry of B-Type Crystal]

The crystal (Crystal form B) obtained by the above describedcrystallization method was crushed in an agate mortar. The obtainedsample was placed on a sample plate for powder X-ray diffractometry, andanalysis was carried out under the conditions shown in Table 7 (FIG. 2).

Measurement Conditions TABLE 7 Sample holder Glass or copper TargetCopper Detector Scintillation counter Tube voltage 40 kV Tube current200 mA Slit DSI/2°, RS0.3 mm, SSI/2° Scanning speed 2°/min Samplinginterval 0.01° Scanning range From 5°to 40° Goniometer Verticalgoniometer

EXAMPLE 72 Synthesis of1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamidefumarate (Crystal form C)

1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamidefumarate (100 mg) was weighed and placed in a round bottom flask. Thecompound was once dissolved in a mixed solvent consisting of water (1ml) and methanol (0.6 ml) while heating. The reaction solution was thenleft at room temperature. The deposited crystal was collected byfiltration. The collected crystal was dried at 60° C., so as to obtainthe subject compound (68 mg).

[Powder X-Ray Diffractometry of C-Type Crystal]

The crystal (C-type crystal) obtained by the above describedcrystallization method was crushed in an agate mortar. The obtainedsample was placed on a sample plate for powder X-ray diffractometry, andanalysis was carried out under the conditions shown in Table 8 (FIG. 3).

Measurement Conditions TABLE 8 Sample holder Glass or copper TargetCopper Detector Scintillation counter Tube voltage 40 kV Tube current200 mA Slit DSI/2°, RS0.3 mm, SSI/2° Scanning speed 2°/min Samplinginterval 0.01° Scanning range From 5° to 40° Goniometer Verticalgoniometer

EXAMPLE 73 Synthesis of1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamidefumarate (D-type crystal)

1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamidefumarate (100 mg) was weighed and placed in a round bottom flask. Thecompound was once dissolved in 2-propanol (1 ml) while heating. Thereaction solution was then left at room temperature. The depositedcrystal was collected by filtration. The collected crystal was dried at60° C., so as to obtain the subject compound (80 mg).

[Powder X-Ray Diffractometry of D-Type Crystal]

The crystal (D-type crystal) obtained by the above describedcrystallization method was crushed in an agate mortar. The obtainedsample was placed on a sample plate for powder X-ray diffractometry, andanalysis was carried out under the conditions shown in Table 9 (FIG. 4).

Measurement Conditions TABLE 9 Sample holder Glass or copper TargetCopper Detector Scintillation counter Tube voltage 40 kV Tube current200 mA Slit DSI/2°, RS0.3 mm, SSI/2° Scanning speed 2°/min Samplinginterval 0.01° Scanning range From 5° to 40° Goniometer Verticalgoniometer

FORMULATION EXAMPLES

Formulation examples of the compound of the present invention will bedescribed below. However, formulation of the compound of the presentinvention is not limited to such formulation examples.

FORMULATION EXAMPLE 1

-   -   Compound in Example 20 45 (parts)    -   Heavy magnesium oxide 15    -   Lactose 75

The above compounds were uniformly mixed, so as to obtain a powder orfine granule powder with a size of 350 μm or less. This powder wasencapsulated in a capsule container, so as to produce a capsule.

FORMULATION EXAMPLE 2

Compound in Example 24 (1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-6-45 (parts) yl)ethyl]peperidin-4-yl}-1H-indole-6- carboxamide) Starch 15Lactose 16 Crystalline cellulose 21 Polyvinyl alcohol  3 Distilled water30

The above compounds were uniformly mixed. The obtained mixture wasgranulated by crushing and then dried. Thereafter, the resultant productwas separated by sieving, so as to produce a granule with a size between1410 and 177 μm.

FORMULATION EXAMPLE 3

A granule was produced by the same method as in Formulation example 2.Thereafter, 4 parts of calcium stearate were added to 96 parts of theabove granule, followed by compression molding, so as to produce atablet with a diameter of 10 mm.

FORMULATION EXAMPLE 4

10 parts of crystalline cellulose and 3 parts of calcium stearate wereadded to 90 parts of the granule obtained by the method described inFormulation example 2. The obtained mixture was subjected to compressionmolding, so as to obtain a table with a diameter of 8 mm. Thereafter, asuspension containing syrup gelatin and precipitated calcium carbonatewas added to the tablet, so as to produce a sugarcoated tablet.

FORMULATION EXAMPLE 5

Compound in Example 22 (1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-0.6 parts yl)ethyl]peperidin-4-yl}-1H-indole-6- carboxamide) Nonionicsurfactant 2.4 Normal saline solution  97

The above components were mixed while heating, and the obtained mixturewas then placed in an ampule. It was then-sterilized, so as to producean injection.

FORMULATION EXAMPLE 6

The compound in Example 20,(1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide,lactose, corn starch, and low substituted hydroxypropylcellulose weremixed. Thereafter, using hydroxypropylcellulose dissolved in anappropriate amount of purified water, wet granulation was carried out.The thus granulated product was dried and then sized. Thereafter, lowsubstituted hydroxypropylcellulose and magnesium stearate were added tothe obtained granule, and these components were then blended, followedby tablet making. The obtained tablet was coated with an aqueoussolution containing a coating base (Opadry yellow). The amounts ofmaterials used per tablet are shown in Table 10. TABLE 10 Material used1 mg tablet 10 mg tablet 60 mg tablet Compound 1 of the  1 mg 10 mg 60mg present invention Lactose 122 mg  113 mg  63 mg Corn starch 20 mg 20mg 20 mg Low substituted 20 mg 20 mg 20 mg hydroxypropylcelluloseHydroxypropylcellulose  6 mg  6 mg  6 mg Purified water AppropriateAppropriate Appropriate amount amount amount Low substituted 10 mg 10 mg10 mg hydroxypropylcellulose Crystalline cellulose 20 mg 20 mg 20 mgMagnesium stearate  1 mg  1 mg  1 mg Opadry yellow (note)  8 mg  8 mg  8mg Total 208 mg  208 mg  208 mg (Note)A premixed material formed by mixing 56% hydroxypropylmethylcellulose2910, 28% talc, 10% Macrogol 6000, 4% titanium oxide, and 2% yellow ironsesquioxide.

The compound represented by general formula (I) of the present inventionhas an effect to bind to a 5-HT1A receptor and also has an antagonisticeffect against to the receptor. Thus, it is useful as an agent fortreating or preventing lower urinary tract symptoms, and particularly,increased urinary frequency, urinary incontinence, or the like.

1. A compound represented by the following formula (I) or apharmacologically acceptable salt thereof:

wherein R¹ and R² are substituents adjacent to each other, and togetherwith two carbon atoms to each of which they attach, form: (1) a 5- to7-membered non-aromatic carbocyclic group, (2) a 5- to 7-memberednon-aromatic heterocyclyl group, (3) a 6-membered aromatic carbocyclicgroup, or (4) a 5- or 6-membered aromatic heterocyclyl group, which maybe substituted by 1 to 4 substituents selected from the followingsubstituent group B1; R³ represents a hydrogen atom or a methyl group;and R⁶ represents a substituent selected from the following substituentgroup A1, Substituent group A1: (1) a hydrogen atom, (2) a halogen atom,(3) a cyano group, (4) a hydroxyl group, (5) a nitro group, (6) acarboxyl group, (7) a C3-C8 cycloalkyl group, (8) a C2-C6 alkenyl group,(9) a C2-C6 alkynyl group, (10) a C1-C6 alkylthio group, (11) a C1-C6alkoxycarbonyl group, (12) a C1-C6 alkylsulfonyl group, (13) a C1-C6alkyl group (wherein said C1-C6 alkyl group may be substituted by 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxyl group, and a C1-C6 alkoxy group), (14) a C1-C6 alkoxy group(wherein said C1-C6 alkoxy group may be substituted by 1 to 3 halogenatoms), (15) an amino group (wherein said amino group may be substitutedby a substituent selected from the group consisting of a C1-C6 alkylgroup, a formyl group, a C1-C6 alkanoyl group, and a C1-C6 alkylsulfonylgroup), and (16) a carbamoyl group (wherein said carbamoyl group may besubstituted by one or two C1-C6 alkyl groups); Substituent group B1: (1)a hydrogen atom, (2) a halogen atom, (3) a cyano group, (4) a hydroxylgroup, (5) a nitro group, (6) an oxo group, (7) a carboxyl group, (8) aC3-C8 cycloalkyl group, (9) a C2-C6 alkenyl group, (10) a C2-C6 alkynylgroup, (11) a C1-C6 alkylthio group, (12) a C1-C6 alkoxycarbonyl group,(13) a C1-C6 alkylsulfonyl group, (14) a C1-C6 alkyl group (wherein saidC1-C6 alkyl group may be substituted by a halogen atom, a hydroxylgroup, and a C1-C6 alkoxy group), (15) a C1-C6 alkoxy group (whereinsaid C1-C6 alkoxy group may be substituted by 1 to 3 halogen atoms),(16) an amino group (wherein said amino group may be substituted by asubstituent selected from the group consisting of a C1-C6 alkyl group, aformyl group, a C1-C6 alkanoyl group, and a C1-C6 alkylsulfonyl group),(17) a carbamoyl group (wherein said carbamoyl group may be substitutedby one or two C1-C6 alkyl groups), (18) a C1-C6 alkoxyimino group, (19)a C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attaching tothe same carbon atom, and (20) a tetrahydropyranyl group formed by twoC1-C3 alkyl group attaching to the same carbon atom, together with anoxygen atom and said carbon atom.
 2. The compound according to claim 1or a pharmacologically acceptable salt thereof, wherein R¹ and R² aresubstituents adjacent to each other, and together with two carbon atomsto each of which they attach, forms a group represented by the followingformula:

wherein a hydrogen atom on each cyclic group may be substituted by 1 to4 substituents selected from the following substituent group B1,Substituent group B1: (1) a hydrogen atom, (2) a halogen atom, (3) acyano group, (4) a hydroxyl group, (5) a nitro group, (6) an oxo group,(7) a carboxyl group, (8) a C3-C8 cycloalkyl group, (9) a C2-C6 alkenylgroup, (10) a C2-C6 alkynyl group, (11) a C1-C6 alkylthio group, (12) aC1-C6 alkoxycarbonyl group, (13) a C1-C6 alkylsulfonyl group, (14) aC1-C6 alkyl group (wherein said C1-C6 alkyl group may be substituted bya halogen atom, a hydroxyl group, and a C1-C6 alkoxy group), (15) aC1-C6 alkoxy group (wherein said C1-C6 alkoxy group may be substitutedby 1 to 3 halogen atoms), (16) an amino group (wherein said amino groupmay be substituted by a substituent selected from the group consistingof a C1-C6 alkyl group, a formyl group, a C1-C6 alkanoyl group, and aC1-C6 alkylsulfonyl group), (17) a carbamoyl group (wherein saidcarbamoyl group may be substituted by one or two C1-C6 alkyl groups),(18) a C1-C6 alkoxyimino group, (19) a C5-C6 cycloalkyl group formed bytwo C1-C3 alkyl groups attaching to the same carbon atom, and (20) atetrahydropyranyl group formed by two C1-C3 alkyl group attaching to thesame carbon atom, together with an oxygen atom and said carbon atom. 3.The compound according to claim 1 or a pharmacologically acceptable saltthereof, which is represented by formula (I-a-1), formula (I-a-2),formula (I-a-3), or formula (I-a-4):

wherein R³ represents a hydrogen atom or methyl group; R4a and R5arepresent substituents selected from the following substituent group B1;R⁶ represents a substituent selected from the following substituentgroup A1; R^(11a) represents a hydroxyl group, R^(12a) represents ahydrogen atom or C1-C6 alkyl group, or R^(11a) and R^(12a) represent acarbonyl group or the formula C═N—OR^(8c) (wherein R^(8c) represents aC1-C6 alkyl group), together with carbon atoms to which R^(11a) andR^(12a) attach; X_(a) represents a methylene group or oxygen atom; andn_(a) represents an integer between 1 and 3, Substituent group A1: (1) ahydrogen atom, (2) a halogen atom, (3) a cyano group, (4) a hydroxylgroup, (5) a nitro group, (6) a carboxyl group, (7) a C3-C8 cycloalkylgroup, (8) a C2-C6 alkenyl group, (9) a C2-C6 alkynyl group, (10) aC1-C6 alkylthio group, (11) a C1-C6 alkoxycarbonyl group, (12) a C1-C6alkylsulfonyl group, (13) a C1-C6 alkyl group (wherein said C1-C6 alkylgroup may be substituted by 1 to 3 substituents selected from the groupconsisting of a halogen atom, a hydroxyl group, and a C1-C6 alkoxygroup), (14) a C1-C6 alkoxy group (wherein said C1-C6 alkoxy group maybe substituted by 1 to 3 halogen atoms), (15) an amino group (whereinsaid amino group may be substituted by a substituent selected from thegroup consisting of a C1-C6 alkyl group, a formyl group, a C1-C6alkanoyl group, and a C1-C6 alkylsulfonyl group), and (16) a carbamoylgroup (wherein said carbamoyl group may be substituted by one or twoC1-C6 alkyl groups); Substituent group B1: (1) a hydrogen atom, (2) ahalogen atom, (3) a cyano group, (4) a hydroxyl group, (5) a nitrogroup, (6) an oxo group, (7) a carboxyl group, (8) a C3-C8 cycloalkylgroup, (9) a C2-C6 alkenyl group, (10) a C2-C6 alkynyl group, (11) aC1-C6 alkylthio group, (12) a C1-C6 alkoxycarbonyl group, (13) a C1-C6alkylsulfonyl group, (14) a C1-C6 alkyl group (wherein said C1-C6 alkylgroup may be substituted by a halogen atom, a hydroxyl group, and aC1-C6 alkoxy group), (15) a C1-C6 alkoxy group (wherein said C1-C6alkoxy group may be substituted by 1 to 3 halogen atoms), (16) an aminogroup (wherein said amino group may be substituted by a substituentselected from the group consisting of a C1-C6 alkyl group, a formylgroup, a C1-C6 alkanoyl group, and a C1-C6 alkylsulfonyl group), (17) acarbamoyl group (wherein said carbamoyl group may be substituted by oneor two C1-C6 alkyl groups), (18) a C1-C6 alkoxyimino group, (19) a C5-C6cycloalkyl group formed by two C1-C3 alkyl groups attaching to the samecarbon atom, and (20) a tetrahydropyranyl group formed by two C1-C3alkyl group attaching to the same carbon atom, together with an oxygenatom and said carbon atom.
 4. The compound according to claim 3 or apharmacologically acceptable salt thereof, wherein R^(11a) and R^(12a)form a carbonyl group, together with carbon atoms to which R^(11a) andR^(12a) attach.
 5. The compound according to claim 3 or apharmacologically acceptable salt thereof, wherein R^(4a) and R^(5a) aresubstituents selected from the following substituent group B2, and R⁶represents a substituent selected from the following substituent groupA2, Substituent group A2: (1) a hydrogen atom, (2) a C1-C6 alkyl group,(3) a halogen atom, (4) a cyano group, (5) a C1-C6 alkoxy group, (6) anamino group wherein a nitrogen atom may be substituted by a C1-C6 alkylgroup, and (7) C1-C6 alkoxy C1-C6 alkyl group; Substituent group B2: (1)a hydrogen atom, (2) a C1-C6 alkyl group, (3) a halogen atom, (4) ahydroxyl group, (5) a C1-C6 alkoxy group, (6) a C1-C6 alkoxy C1-C6 alkylgroup, (7) a C5-C6 cycloalkyl group formed by two C1-C3 alkyl groupsattaching to the same carbon atom, and (8) a tetrahydropyranyl groupformed by two C1-C3 alkyl group attaching to the same carbon atom,together with an oxygen atom and said carbon atom.
 6. The compoundaccording to claim 3 or a pharmacologically acceptable salt thereof,wherein R^(4a) and R^(5a) represent substituents selected from thefollowing substituent group B5, and R⁶ represents a substituent selectedfrom the following substituent group A4, Substituent group A4: (1) ahydrogen atom, and (2) a C1-C6 alkoxy group; Substituent group B5: (1) ahydrogen atom, (2) a C1-C6 alkyl group, (3) a C1-C6 alkoxy C1-C6 agroup, (4) a C5-C6 cycloalkyl group formed by two C1-C3 alkyl groupsattaching to the same carbon atom, and (5) a tetrahydropyranyl groupformed by two C1-C3 alkyl group attaching to the same carbon atom,together with an oxygen atom and said carbon atom.
 7. The compoundaccording to claim 3 or a pharmacologically acceptable salt thereof,wherein X_(a) represents an oxygen atom.
 8. The compound according toclaim 1 or a pharmacologically acceptable salt thereof, which isrepresented by formula (I-b-1), formula (I-b-2), formula (I-b-3), orformula (I-b-4):

wherein R^(4a) and R^(5a) represent substituents selected from thefollowing substituent group B5, and R⁶ represents a substituent selectedfrom the following substituent group A4, Substituent group A4: (1) ahydrogen atom, and (2) a C1-C6 alkoxy group; Substituent group B5: (1) ahydrogen atom, (2) a C1-C6 alkyl group, (3) a C1-C6 alkoxy C1-C6 alkylgroup, (4) a C5-C6 cycloalkyl group formed by two C1-C3 alkyl groupsattaching to the same carbon atom, and (5) a tetrahydropyranyl groupformed by two C1-C3 alkyl group attaching to the same carbon atom,together with an oxygen atom and said carbon atom.
 9. The compoundaccording to claim 3 or a pharmacologically acceptable salt thereof,wherein R^(11a) represents a hydroxyl group, and R^(12a) represents ahydrogen atom or C1-C6 alkyl group.
 10. The compound according to claim9 or a pharmacologically acceptable salt thereof, wherein R^(4a) andR^(5a) are substituents selected from the following substituent groupB2, and R⁶ represents a substituent selected from the followingsubstituent group A2, Substituent group A2: (1) a hydrogen atom, (2) aC1-C6 alkyl group, (3) a halogen atom, (4) a cyano group, (5) a C1-C6alkoxy group, (6) an amino group wherein a nitrogen atom may besubstituted by a C1-C6 alkyl group, and (7) C1-C6 alkoxy C1-C6 alkylgroup; Substituent group B2: (1) a hydrogen atom, (2) a C1-C6 alkylgroup, (3) a halogen atom, (4) a hydroxyl group, (5) a C1-C6 alkoxygroup, (6) a C1-C6 alkoxy C1-C6 alkyl group, (7) a C5-C6 cycloalkylgroup formed by two C1-C3 alkyl groups attaching to the same carbonatom, and (8) a tetrahydropyranyl group formed by two C1-C3 alkyl groupattaching to the same carbon atom, together with an oxygen atom and saidcarbon atom.
 11. The compound according to claim 9 or apharmacologically acceptable salt thereof, wherein X_(a) represents anoxygen atom.
 12. The compound according to claim 3 or apharmacologically acceptable salt thereof, wherein R^(11a) and R^(12a)together form the formula ═N—OR^(8c) (wherein R^(8c) represents a C1-C6alkyl group).
 13. The compound according to claim 12 or apharmacologically acceptable salt thereof, wherein R^(4a) and R^(5a) aresubstituents selected from the following substituent group B3, and R⁶represents a substituent selected from the following substituent groupA2, Substituent group A2: (1) a hydrogen atom, (2) a C1-C6 alkyl group,(3) a halogen atom, (4) a cyano group, (5) a C1-C6 alkoxy group, (6) anamino group wherein a nitrogen atom may be substituted by a C1-C6 alkylgroup, and (7) C1-C6 alkoxy C1-C6 alkyl group; Substituent group B3: (1)a hydrogen atom, (2) a C1-C6 alkyl group, (3) a halogen atom, (4) ahydroxyl group, (5) a C1-C6 alkoxy group, and (6) a C1-C6 alkoxy C1-C6alkyl group.
 14. The compound according to claim 12 or apharmacologically acceptable salt thereof, wherein X_(a) represents anoxygen atom.
 15. The compound according to claim 1 or apharmacologically acceptable salt thereof, which is represented byformula (I-c-1) or formula (I-c-2):

wherein R³ represents a hydrogen atom or methyl group; and R^(4d),R^(5d), and R⁶ represent substituents selected from the followingsubstituent group A1, Substituent group A1: (1) a hydrogen atom, (2) ahalogen atom, (3) a cyano group, (4) a hydroxyl group, (5) a nitrogroup, (6) a carboxyl group, (7) a C3-C8 cycloalkyl group, (8) a C2-C6alkenyl group, (9) a C2-C6 alkynyl group, (10) a C1-C6 alkylthio group,(11) a C1-C6 alkoxycarbonyl group, (12) a C1-C6 alkylsulfonyl group,(13) a C1-C6 alkyl group (wherein said C1-C6 alkyl group may besubstituted by 1 to 3 substituents selected from the group consisting ofa halogen atom, a hydroxyl group, and a C1-C6 alkoxy group), (14) aC1-C6 alkoxy group (wherein said C1-C6 alkoxy group may be substitutedby 1 to 3 halogen atoms), (15) an amino group (wherein said amino groupmay be substituted by a substituent selected from the group consistingof a C1-C6 alkyl group, a formyl group, a C1-C6 alkanoyl group, and aC1-C6 alkylsulfonyl group), and (16) a carbamoyl group (wherein saidcarbamoyl group may be substituted by one or two C1-C6 alkyl groups).16. The compound according to claim 15 or a pharmacologically acceptablesalt thereof, wherein R^(4d) and R^(5d) are substituents selected fromthe following substituent group B4, and R⁶ represents a substituentselected from the following substituent group A2, Substituent group A2:(1) a hydrogen atom, (2) a C1-C6 alkyl group, (3) a halogen atom, (4) acyano group, (5) a C1-C6 alkoxy group, (6) an amino group wherein anitrogen atom may be substituted by a C1-C6 alkyl group, and (7) C1-C6alkoxy C1-C6 alkyl group; Substituent group B4: (1) a hydrogen atom, (2)a C1-C6 alkyl group, (3) a C1-C6 alkoxy group, and (4) a C1-C6 alkoxyC1-C6 alkyl group.
 17. The compound according to claim 1 or apharmacologically acceptable salt thereof, which is represented byformula (I-d-1) or formula (I-d-2):

wherein R³ represents a hydrogen atom or methyl group; R^(4e) and R^(5e)represent substituents selected from the following substituent group A1;R⁶ represents a substituent selected from the following substituentgroup A1; and each of X_(e) and Y_(e) represents (1) an oxygen atom, (2)a methylene group, (3) —CONR^(7e)— (wherein R^(7e) represents (1) ahydrogen atom, or (2) a C1-C6 alkyl group), (4) —NR^(7e)CO— (whereinR^(7e) has the same above meaning), (5) —NR^(8e)— (wherein R^(8e)represents (1) a C1-C6 alkyl group, or (2) a C1-C6 acyl group), or (6) asingle bond, Substituent group A1: (1) a hydrogen atom, (2) a halogenatom, (3) a cyano group, (4) a hydroxyl group, (5) a nitro group, (6) acarboxyl group, (7) a C3-C8 cycloalkyl group, (8) a C2-C6 alkenyl group,(9) a C2-C6 alkynyl group, (10) a C1-C6 alkylthio group, (11) a C1-C6alkoxycarbonyl group, (12) a C1-C6 alkylsulfonyl group, (13) a C1-C6alkyl group (wherein said C1-C6 alkyl group may be substituted by 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxyl group, and a C1-C6 alkoxy group), (14) a C1-C6 alkoxy group(wherein said C1-C6 alkoxy group may be substituted by 1 to 3 halogenatoms), (15) an amino group (wherein said amino group may be substitutedby a substituent selected from the group consisting of a C1-C6 alkylgroup, a formyl group, a C1-C6 alkanoyl group, and a C1-C6 alkylsulfonylgroup), and (16) a carbamoyl group (wherein said carbamoyl group may besubstituted by one or two C1-C6 alkyl groups).
 18. The compoundaccording to claim 17 or a pharmacologically acceptable salt thereof,wherein R4e and R5e are substituents selected from the followingsubstituent group B3, and R⁶ represents a substituent selected from thefollowing substituent group A2, Substituent group A2: (1) a hydrogenatom, (2) a C1-C6 alkyl group, (3) a halogen atom, (4) a cyano group,(5) a C1-C6 alkoxy group, (6) an amino group wherein a nitrogen atom maybe substituted by a C1-C6 alkyl group, and (7) C1-C6 alkoxy C1-C6 alkylgroup; Substituent group B3: (1) a hydrogen atom, (2) a C1-C6 alkylgroup, (3) a halogen atom, (4) a hydroxyl group, (5) a C1-C6 alkoxygroup, and (6) a C1-C6 alkoxy C1-C6 alkyl group.
 19. The compoundaccording to claim 1 or a pharmacologically acceptable salt thereof,which is represented by formula (I-e-1) or formula (I-e-2):

wherein R³ represents a hydrogen atom or methyl group; R⁶ represents asubstituent selected from the following substituent group A1; R^(7f)represents (1) hydrogen atom, (2) a C1-C6 alkyl group, (3) a C3-C8cycloalkyl group, (4) a C2-C6 alkenyl group, (5) a C2-C6 alkynyl group,or (6) a C1-C6 alkoxy C1-C6 alkyl group; and each of X_(f) and Y_(f)represents (1) a single bond, (2) a methylene group which may have asubstituent selected from the following substituent group A1, or (3) acarbonyl group, Substituent group A1: (1) a hydrogen atom, (2) a halogenatom, (3) a cyano group, (4) a hydroxyl group, (5) a nitro group, (6) acarboxyl group, (7) a C3-C8 cycloalkyl group, (8) a C2-C6 alkenyl group,(9) a C2-C6 alkynyl group, (10) a C1-C6 alkylthio group, (11) a C1-C6alkoxycarbonyl group, (12) a C1-C6 alkylsulfonyl group, (13) a C1-C6alkyl group (wherein said C1-C6 alkyl group may be substituted by 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxyl group, and a C1-C6 alkoxy group), (14) a C1-C6 alkoxy group(wherein said C1-C6 alkoxy group may be substituted by 1 to 3 halogenatoms), (15) an amino group (wherein said amino group may be substitutedby a substituent selected from the group consisting of a C1-C6 alkylgroup, a formyl group, a C1-C6 alkanoyl group, and a C1-C6 alkylsulfonylgroup), and (16) a carbamoyl group (wherein said carbamoyl group may besubstituted by one or two C1-C6 alkyl groups).
 20. The compoundaccording to claim 19 or a pharmacologically acceptable salt thereof,wherein R⁶ represents a substituent selected from the followingsubstituent group A2; R^(7f) represents a substituent selected from thefollowing substituent group B4; and each of X_(f) and Y_(f) represents(1) a single bond, (2) a methylene group which may have a substituentselected from the following substituent group B4, or (3) a carbonylgroup, Substituent group A2: (1) a hydrogen atom, (2) a C1-C6 alkylgroup, (3) a halogen atom, (4) a cyano group, (5) a C1-C6 alkoxy group,(6) an amino group wherein a nitrogen atom may be substituted by a C1-C6alkyl group, and (7) C1-C6 alkoxy C1-C6 alkyl group; Substituent groupB4: (1) a hydrogen atom, (2) a C1-C6 alkyl group, and (3) C1-C6 alkoxygroup (4) a C1-C6 alkoxy C1-C6 alkyl group.
 21. The compound accordingto claim 1 or a pharmacologically acceptable salt thereof, which isrepresented by formula (I-f-1), formula (I-f-2), formula (I-f-3),formula (I-f-4), formula (I-g-1), formula (I-g-2), formula (I-h-1),formula (I-h-2), formula (I-h-3), or formula (I-h-4):

wherein R³ represents a hydrogen atom or methyl group; and R⁶ and R^(7g)represent substituents selected from the following substituent group A1(however, a case where R⁷ ^(g) represents a hydroxyl group is excluded),Substituent group A1: (1) a hydrogen atom, (2) a halogen atom, (3) acyano group, (4) a hydroxyl group, (5) a nitro group, (6) a carboxylgroup, (7) a C3-C8 cycloalkyl group, (8) a C2-C6 alkenyl group, (9) aC2-C6 alkynyl group, (10) a C1-C6 alkylthio group, (11) a C1-C6alkoxycarbonyl group, (12) a C1-C6 alkylsulfonyl group, (13) a C1-C6alkyl group (wherein said C1-C6 alkyl group may be substituted by 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxyl group, and a C1-C6 alkoxy group), (14) a C1-C6 alkoxy group(wherein said C1-C6 alkoxy group may be substituted by 1 to 3 halogenatoms), (15) an amino group (wherein said amino group may be substitutedby a substituent selected from the group consisting of a C1-C6 alkylgroup, a formyl group, a C1-C6 alkanoyl group, and a C1-C6 alkylsulfonylgroup), and (16) a carbamoyl group (wherein said carbamoyl group may besubstituted by one or two C1-C6 alkyl groups).
 22. The compoundaccording to claim 21 or a pharmacologically acceptable salt thereof,wherein R⁶ represents a substituent selected from the followingsubstituent group A2, and R^(7g) represents a substituent selected fromthe following substituent group B7, Substituent group A2: (1) a hydrogenatom, (2) a C1-C6 alkyl group, (3) a halogen atom, (4) a cyano group,(5) a C1-C6 alkoxy group, (6) an amino group wherein a nitrogen atom maybe substituted by a C1-C6 alkyl group, and (7) C1-C6 alkoxy C1-C6 alkylgroup; Substituent group B7: (1) a hydrogen atom, (2) a C1-C6 alkylgroup, (3) a halogen atom, (4) a cyano group, and (5) a C1-C6 alkoxyC1-C6 alkyl group.
 23. The compound according to claim 21 or apharmacologically acceptable salt thereof, wherein R⁶ represents asubstituent selected from the following substituent group A4, and R^(7g)represents a substituent selected from the following substituent groupB6, Substituent group A4: (1) a hydrogen atom, and (2) a C1-C6 alkoxygroup; Substituent group B6: (1) a hydrogen atom, and (2) a C1-C6 alkylgroup.
 24. The compound according to claim 1 or a pharmacologicallyacceptable salt thereof, which is represented by formula (I-i-1) orformula (I-i-2):

wherein R³ represents a hydrogen atom or methyl group; and R⁶, R^(9h),and R^(10h) represent substituents selected from the followingsubstituent group A1; and X_(h) and Y_(h) represent (1) a methine groupor (2) a nitrogen atom, Substituent group A1: (1) a hydrogen atom, (2) ahalogen atom, (3) a cyano group, (4) a hydroxyl group, (5) a nitrogroup, (6) a carboxyl group, (7) a C3-C8 cycloalkyl group, (8) a C2-C6alkenyl group, (9) a C2-C6 alkynyl group, (10) a C1-C6 alkylthio group,(11) a C1-C6 alkoxycarbonyl group, (12) a C1-C6 alkylsulfonyl group,(13) a C1-C6 alkyl group (wherein said C1-C6 alkyl group may besubstituted by 1 to 3 substituents selected from the group consisting ofa halogen atom, a hydroxyl group, and a C1-C6 alkoxy group), (14) aC1-C6 alkoxy group (wherein said C1-C6 alkoxy group may be substitutedby 1 to 3 halogen atoms), (15) an amino group (wherein said amino groupmay be substituted by a substituent selected from the group consistingof a C1-C6 alkyl group, a formyl group, a C1-C6 alkanoyl group, and aC1-C6 alkylsulfonyl group), and (16) a carbamoyl group (wherein saidcarbamoyl group may be substituted by one or two C1-C6 alkyl groups).25. The compound according to claim 24 or a pharmacologically acceptablesalt thereof, wherein R^(9h), R^(10h), and R⁶ represent substituentsselected from the following substituent group A2; and X_(h) and Y_(h)represent (1) a methine group or (2) a nitrogen atom, Substituent groupA2: (1) a hydrogen atom, (2) a C1-C6 alkyl group, (3) a halogen atom,(4) a cyano group, (5) a C1-C6 alkoxy group, (6) an amino group whereina nitrogen atom may be substituted by a C1-C6 alkyl group, and (7) C1-C6alkoxy C1-C6 alkyl group.
 26. The compound according to claim 1 selectedfrom the following group or a pharmacologically acceptable saltthereof: 1)1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide,2)1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,3)1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-6-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,4)1-{1-[2-(6-Methoxy-3-oxoindan-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,5)1-{1-[2-(6-Methoxy-2-methylbenzoxazol-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,6)1-{1-[2-(6-Methoxy-2-methylbenzoxazol-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,7)1-{1-[2-(6-Methoxy-3-methylbenzo[d]isoxazol-5-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,8)1-{1-[2-(6-Methoxy-3-methylbenzo[d]isoxazol-7-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,9)1-{1-[2-(5-Methoxy-1-oxoindan-4-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,and 10)1-{1-[2-(7-Methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide.27. The compound according to claim 1 selected from the following groupor a pharmacologically acceptable salt thereof: 1)1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-N-methyl-1H-indole-6-carboxamide,2)1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide,and 3) 1-{1-[2-(7-Methoxy-2,2-dimethyl-4-oxochroman-6-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxamide.28. A pharmaceutical composition comprising, as an active ingredient, acompound represented by the following formula (I) or a pharmacologicallyacceptable salt thereof:

wherein R¹ and R² are substituents adjacent to each other, and togetherwith two carbon atoms to each of which they attach, form: (1) a 5- to7-membered non-aromatic carbocyclic group, (2) a 5- to 7-memberednon-aromatic heterocyclyl group, (3) a 6-membered aromatic carbocyclicgroup, or (4) a 5- or 6-membered aromatic heterocyclyl group, which maybe substituted by 1 to 4 substituents selected from the followingsubstituent group B1; R³ represents a hydrogen atom or methyl group; andR⁶ represents a substituent selected from the following substituentgroup A1, Substituent group A1: (1) a hydrogen atom, (2) a halogen atom,(3) a cyano group, (4) a hydroxyl group, (5) a nitro group, (6) acarboxyl group, (7) a C3-C8 cycloalkyl group, (8) a C2-C6 alkenyl group,(9) a C2-C6 alkynyl group, (10) a C1-C6 alkylthio group, (11) a C1-C6alkoxycarbonyl group, (12) a C1-C6 alkylsulfonyl group, (13) a C1-C6alkyl group (wherein said C1-C6 alkyl group may be substituted by 1 to 3substituents selected from the group consisting of a halogen atom, ahydroxyl group, and a C1-C6 alkoxy group), (14) a C1-C6 alkoxy group(wherein said C1-C6 alkoxy group may be substituted by 1 to 3 halogenatoms), (15) an amino group (wherein said amino group may be substitutedby a substituent selected from the group consisting of a C1-C6 alkylgroup, a formyl group, a C1-C6 alkanoyl group, and a C1-C6 alkylsulfonylgroup), and (16) a carbamoyl group (wherein said carbamoyl group may besubstituted by one or two C1-C6 alkyl groups); Substituent group B1: (1)a hydrogen atom, (2) a halogen atom, (3) a cyano group, (4) a hydroxylgroup, (5) a nitro group, (6) an oxo group, (7) a carboxyl group, (8) aC3-C8 cycloalkyl group, (9) a C2-C6 alkenyl group, (10) a C2-C6 alkynylgroup, (11) a C1-C6 alkylthio group, (12) a C1-C6 alkoxycarbonyl group,(13) a C1-C6 alkylsulfonyl group, (14) a C1-C6 alkyl group (wherein saidC1-C6 alkyl group may be substituted by a halogen atom, a hydroxylgroup, and a C1-C6 alkoxy group), (15) a C1-C6 alkoxy group (whereinsaid C1-C6 alkoxy group may be substituted by 1 to 3 halogen atoms),(16) an amino group (wherein said amino group may be substituted by asubstituent selected from the group consisting of a C1-C6 alkyl group, aformyl group, a C1-C6 alkanoyl group, and a C1-C6 alkylsulfonyl group),(17) a carbamoyl group (wherein said carbamoyl group may be substitutedby one or two C1-C6 alkyl groups), (18) a C1-C6 alkoxyimino group, (19)a C5-C6 cycloalkyl group formed by two C1-C3 alkyl groups attaching tothe same carbon atom, and (20) a tetrahydropyranyl group formed by twoC1-C3 alkyl group attaching to the same carbon atom, together with anoxygen atom and said carbon atom.
 29. The pharmaceutical compositionaccording to claim 28 characterized in that it is an agent for treatingor preventing lower urinary tract symptoms.
 30. The pharmaceuticalcomposition according to claim 29 characterized in that it is an agentfor treating or preventing symptoms regarding urinary storage.
 31. Thepharmaceutical composition according to claim 29 characterized in thatit is an agent for treating or preventing increased urinary frequency orurinary incontinence.
 32. The pharmaceutical composition according toclaim 28 characterized in that it is an agent for treating or preventingcognitive impairment which are associated with Alzheimer's disease orsenile dementia, learning or memory disorder, or anxiety disorder. 33.The pharmaceutical composition according to claim 28 characterized inthat it is an agent for treating or preventing schizophrenia, emotionaldisorder, alcohol and/or cocaine dependence, symptoms associated withwithdrawal from nicotine ingestion or smoking, or visual attentiondisorder.
 34. The pharmaceutical composition according to claim 28characterized in that it is an agent for treating or preventing sleepdisorder, migraine, temperature instability, eating disorder, vomiting,gastrointestinal disorder, or genital insufficiency.